Cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals

ABSTRACT

The present invention relates to cyclic indole-3-carboxamides of the formula I, 
     
       
         
         
             
             
         
       
     
     wherein A, R, R 10 , R 20 , R 30 , R 40 , n, p and q have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. Specifically, they inhibit the enzyme renin and modulate the activity of the renin-angiotensin system, and are useful for the treatment of diseases such as hypertension, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use and pharmaceutical compositions comprising them.

FIELD OF THE INVENTION

The present invention relates to cyclic indole-3-carboxamides of theformula I,

wherein A, R, R¹⁰, R²⁰, R³⁰, R⁴⁰, n, p and q have the meanings indicatedbelow, which are valuable pharmaceutical active compounds. Specifically,they inhibit the enzyme renin and modulate the activity of therenin-angiotensin system, and are useful for the treatment of diseasessuch as hypertension, for example. The invention furthermore relates toprocesses for the preparation of the compounds of the formula I, theiruse and pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

The renin-angiotensin system (RAS; also designated as renin-angiotensinaldosterone system, RAAS) is a key regulator of cardiovascular functionsas well as for the balance of electrolytes and for maintaining bodyfluid volume, and a determinant of blood pressure (cf., for example, E.Lonn, Can. J. Cardiol. 20 (Suppl. B) (2004), 83B; I. A. Reid, Am. J.Physiol.: Advances in Physiology Education 20 (1998), S236). It acts viathe effects of angiotensin II, an octapeptide hormone, which binds toangiotensin receptors. The formation of angiotensin II involves two mainsteps. In the first step, renin (EC 3.4.23.15; formerly EC 3.4.99.19 andEC 3.4.4.15), a 340 amino acid aspartyl proteinase, cleavesangiotensinogen to form the biologically inactive decapeptideangiotensin I. In the second step, angiotensin I is converted intoangiotensin II by the zinc-dependent protease angiotensin-convertingenzyme (ACE).

Renin is produced in the juxtaglomerular cells of the kidney primarilyin the form of the biologically inactive prorenin. Its release from thekidney and activation and subsequent RAS activation in normotensivehumans is stimulated by sodium or volume depletion, or by a reduction inblood pressure.

RAS activity is the principal determinant of several pathological statessince angiotensin II, the major effector molecule of this system,increases blood pressure both directly by arterial vasoconstriction andindirectly by liberating the sodium-retaining hormone aldosterone fromthe adrenal glands, accompanied by an increase in extracellular fluidvolume, as well as having growth-promoting effects on vascular, cardiacand renal tissues which contribute to end-organ damage.

Pharmacological blockade of the RAS is an established way of treatingvarious diseases, for example hypertension (cf., for example, Handbookof Hypertension, W. H. Birkenhäger et al. (ed.), Elsevier SciencePublishers, Amsterdam (1986), vol. 8, 489). However, the therapeuticresponse achieved with the currently used types of RAS blockers, ACEinhibitors and angiotensin receptor blockers, although efficacious, islimited. This may be due to the rise in renin which is induced by theseagents and results in an increase in angiotensin I which can beconverted into angiotensin II via other pathways than by means of ACE.An inhibition of renin, which controls the initial and rate-limitingstep in the RAS by catalyzing the cleavage of the Leu10-Val11 peptidebond of angiotensinogen resulting in the formation of the angiotensinpeptides, would inhibit the complete RAS and thus be more efficient.Furthermore, whereas inhibition of ACE also affects the level of otherpeptides which are cleaved by ACE such as bradykinin, for example, whichis associated with side effects of ACE inhibitors like cough orangioedema, renin is specific in that angiotensinogen is its onlynatural substrate. Inhibition of renin thus offers a specific andpowerful way of lowering blood pressure (cf. M. Moser et al., J. Clin.Hypertension, 9 (2007), 701) as well as providing organ protection oforgans such as the heart, kidney and brain and, besides for treatinghypertension, thus is useful for treating disorders of thecardiovascular system, such as heart failure, cardiac insufficiency,cardiac failure, cardiac infarction, cardiac hypertrophy, vascularhypertrophy, left ventricular dysfunction, in particular leftventricular dysfunction after myocardial infarction, restenosis andangina pectoris; renal diseases, such as renal fibrosis, renal failureand kidney insufficiency; diabetes complications, such as nephropathyand retinopathy; glaucoma; and cerebral afflictions, such as cerebralhemorrhage, for example (with respect to the effect of the RAS on renaldiseases and cardiac damage, cf., for example, U. C. Brewster, Am. J.Med. 116 (2004), 263; J. Gaedeke et al., Expert Opin. Pharmacother. 7(2006), 377; B. Pilz et al., Hypertension 46 (2005), 569).

A large number of peptidic and peptidomimetic inhibitors of human reninwith various stable transition-state analogues of the scissile peptidebond have been developed since about 1980 and contributed to thevalidation of renin as a therapeutic target (cf., for example, B. B.Scott et al., Curr. Protein Pept. Sci. 7 (2006), 241; J. Maibaum et al.,Expert Opin. Ther. Patents 13 (2003), 589). However, these compoundsgenerally suffer from deficiencies such as insufficient bioavailability(cf. H. D. Kleinert, Cardiovasc. Drugs Therapy 9 (1985), 645) orduration of action, or high cost of production. Recently, an orallyactive renin inhibitor, aliskiren (cf. Drugs Fut. 26 (2001), 1139; J.Wood et al., J. Hypertens. 23 (2005), 417; M. Azizi et al., J.Hypertens. 24 (2006), 243) has been marketed. But the property profileof aliskiren is not yet ideal, for example with respect to oralbioavailability, and a particular drawback of aliskiren is its complexmolecular structure with four chiral centers and its multistepsynthesis. Thus, there is still a great need for new, non-peptidic smallmolecule renin inhibitors which exhibit favorable properties, forexample with respect to oral bioavailability or low molecular complexityand simple synthetic access. The present invention satisfies this needby providing the renin-inhibiting cyclic indole-3-carboxamides of theformula I.

Various indole derivatives have already been described. For example, inUS 2005/0054631 and U.S. Pat. No. 4,148,895 certain indole derivativesare described which comprise an amino group in the 2-position of theindole ring and which are inhibitors of poly(adenosine 5′-diphosphateribose)polymerase (PARP) useful for the treatment of a variety ofdiseases including diseases associated with the central nervous systemand cardiovascular disorders, or exhibit hypotensive and especiallyantiarrhythmic activity, respectively. In EP 1452525 indole derivativesare described which, among others, can contain in the 3-position of theindole ring a carboxamide group wherein the amide nitrogen atom is aring member of a diazacycloalkane which carries on the second ringnitrogen atom a pyridine, pyrazine, pyridazine or pyrimidine group, andwhich are inhibitors of transforming growth factor β (TGF-β) useful forthe treatment of fibroproliferative disorders, for example. Similarindole-3-carboxamide derivatives which are inhibitors of TGF-β and areuseful for the treatment of fibroproliferative disorders or specificallyfor the treatment of nephritis, are described in EP 1156045 and EP1243268. WO 2005/121175 relates to CD4 mimetic compounds, among themindole derivatives which can contain a carboxamide group the amidenitrogen atom of which is a member of a ring, which complex withenvelope proteins of human immunodeficiency virus and are useful foreliciting an immune response. WO 99/43672, WO 99/43654 and U.S. Pat. No.6,500,853 relate in a very broad manner to derivatives of indole,indoline and other heterocycles, among them indolecarboxamides, whichare phospholipase A₂ inhibitors and are useful for the treatment ofinflammatory conditions. The indole-3-carboxamides of the presentinvention, wherein the amide nitrogen atom is a ring member of a 1,4- or1,5-diazacycloalkane ring system, the nitrogen atom in position 1 of theindole ring system carries a cyclic group, and the carbon atom inposition 2 of the indole ring system is linked to a (hetero)aromaticgroup, have not yet been disclosed.

DESCRIPTION OF THE INVENTION

Thus, a subject of the present invention are the compounds of theformula I, in any of their stereoisomeric forms or a mixture ofstereoisomeric forms in any ratio, and the physiologically acceptablesalts thereof, and the physiologically acceptable solvates of any ofthem,

whereinA is chosen from O, S, N((C₁-C₄)-alkyl) and C(R^(a))₂;R^(a) is chosen from hydrogen, fluorine and (C₁-C₄)-alkyl, wherein thetwo groups R^(a) are independent of each other and can be identical ordifferent, or the two groups R^(a) together are a divalent (C₂-C₈)-alkylgroup;

R is chosen from hydrogen, fluorine, (C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl-, heteroaryl-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)—, R¹—NH—CO—C_(u)H_(2u)— and(C₁-C₄)-alkyl-O—, wherein all groups R are independent of each other andcan be identical or different;

R¹ is chosen from hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andH₂N—CO—(C₁-C₄)-alkyl-;R¹⁰ is chosen from hydrogen, (C₁-C₆)-alkyl-O—CO— and(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—;R²⁰ is chosen from phenyl and heteroaryl which are optionallysubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—,hydroxy and cyano;R³⁰ is chosen from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,tetrahydropyranyl, phenyl and heteroaryl, wherein cycloalkyl andcycloalkenyl are optionally substituted by one or more identical ordifferent substituents chosen from fluorine, (C₁-C₄)-alkyl and hydroxy,and phenyl and heteroaryl are optionally substituted by one or moreidentical or different substituents chosen from halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, hydroxy-(C₁-C₆)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₆)-alkyl-,(C₁-C₄)-alkyl-CO—NH—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—, hydroxy-(C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-CO—NH—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano;R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, phenyl-(C₁-C₄)-alkyl-,heteroaryl-(C₁-C₄)-alkyl-, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₄)-alkyl-,phenyl-O—(C₁-C₄)-alkyl-, heteroaryl-O—(C₁-C₄)-alkyl-,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-, HO—CO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-, H₂N—CO—(C₁-C₄)-alkyl-, hydroxy,(C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—,phenyl-(C₁-C₄)-alkyl-O—, heteroaryl-(C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, heteroaryl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—, H₂N—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—CO—O—,(C₁-C₄)-alkyl-NH—CO—O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—NH—CO—O—,(C₁-C₄)-alkyl-S(O)_(m)—, nitro, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkyl-CO—NH—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—CO—NH—, (C₁-C₄)-alkyl-S(O)₂—NH—, HO—CO—,(C₁-C₄)-alkyl-O—CO—, H₂N—CO—, ((C₁-C₄)-alkyl)-NH—CO—,di((C₁-C₄)-alkyl)N—CO—, cyano, HO—S(O)₂—, H₂N—S(O)₂—,((C₁-C₄)-alkyl)-NH—S(O)₂— and di((C₁-C₄)-alkyl)N—S(O)₂—, wherein allsubstituents R⁴⁰ are independent of each other and can be identical ordifferent;heteroaryl is an aromatic monocyclic, 5-membered or 6-membered,heterocyclic group which comprises 1, 2 or 3 identical or different ringheteroatoms chosen from N, O and S, wherein one of the ring nitrogenatoms can carry a hydrogen atom or a (C₁-C₄)-alkyl group, and whereinthe heteroaryl group is bonded via a ring carbon atom;m is chosen from 0, 1 and 2, wherein all numbers m are independent ofeach other and can be identical or different;n is chosen from 0, 1, 2, 3 and 4;p and q, which are independent of each other and can be identical ordifferent, are chosen from 2 and 3;u is chosen from 0, 1 and 2, wherein all numbers u are independent ofeach other and can be identical or different;v is chosen from 0, 1 and 2, wherein all numbers v are independent ofeach other and can be identical or different;wherein all alkyl groups, independently of each other, are optionallysubstituted by one or more fluorine atoms;wherein all cycloalkyl groups, independently of each other, areoptionally substituted by one or more identical or differentsubstituents chosen from fluorine and (C₁-C₄)-alkyl, unless specifiedotherwise;wherein all phenyl and heteroaryl groups present in R and R⁴⁰,independently of each other, are optionally substituted by one or moreidentical or different substituents chosen from halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)₂— and cyano.

If structural elements such as groups, substituents or numbers can occurseveral times in the compounds of the formula I, they are allindependent of one another and can in each case have any of theindicated meanings, and can in each case be identical to or differentfrom any other such element.

Alkyl groups, i.e. saturated hydrocarbon residues, can be straight-chain(linear) or branched. This also applies if these groups are substitutedor are part of another group, for example an alkyl-O— group (alkyloxygroup, alkoxy group) or an alkyl-S(O)_(m)— group. Depending on therespective definition, the number of carbon atoms in an alkyl group canbe 1, 2, 3, 4, 5, 6, 7 or 8. Examples of alkyl are methyl, ethyl, propylincluding n-propyl and isopropyl, butyl including n-butyl, sec-butyl,isobutyl and tert-butyl, pentyl including n-pentyl, 1-methylbutyl,isopentyl, neopentyl and tert-pentyl, hexyl including n-hexyl,3,3-dimethylbutyl and isohexyl, heptyl including n-heptyl, and octylincluding n-octyl. Examples of alkyl-O— are methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy and n-pentoxy. Examples ofalkyl-S(O)_(m)— are methanesulfanyl-(CH₃—S—, methylsulfanyl),methanesulfinyl-(CH₃—S(O)—), methanesulfonyl-(CH₃—S(O)₂—),ethanesulfanyl-(CH₃—CH₂—S—, ethylsulfanyl-),ethanesulfinyl-(CH₃—CH₂—S(O)—), ethanesulfonyl-(CH₃—CH₂—S(O)₂—),1-methylethanesulfanyl-((CH₃)₂CH—S—, 1-methylethylsulfanyl-),1-methylethanesulfinyl-((CH₃)₂CH—S(O)—) and1-methylethanesulfonyl-((CH₃)₂CH—S(O)₂—). In one embodiment of theinvention the number m is chosen from 0 and 2, wherein all numbers m areindependent of each other and can be identical or different.

A substituted alkyl group can be substituted in any positions, providedthat the resulting compound is sufficiently stable and is suitable as apharmaceutical active compound. The prerequisite that a specific groupand a compound of the formula I are sufficiently stable and suitable asa pharmaceutical active compound, applies in general with respect to allgroups in the compounds of the formula I. If an alkyl group can bemonosubstituted or polysubstituted by fluorine, it can be unsubstituted,i.e. not carry fluorine atoms, or substituted, for example by 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or 11 fluorine atoms, preferably by 1, 2, 3, 4 or 5fluorine atoms, which can be present in any positions. For example, in afluoro-substituted alkyl group one or more methyl groups can carry threefluorine atoms each and be present as trifluoromethyl groups, and/or oneor more methylene groups (CH₂) can carry two fluorine atoms each and bepresent as difluoromethylene groups. The explanations with respect tothe substitution of a group by fluorine also apply if the groupadditionally carries other substituents and/or is part of another group,for example of an alkyl-O— group. Examples of fluoro-substituted alkylgroups are trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl andheptafluoroisopropyl. Examples of fluoro-substituted alkyl-O— groups aretrifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and3,3,3-trifluoropropoxy. Examples of fluoro-substituted alkyl-S(O)_(m)—groups are trifluoromethanesulfanyl-(CF₃—S—, trifluoromethylsulfanyl-),trifluoromethanesulfinyl-(CF₃—S(O)—) andtrifluoromethanesulfonyl-(CF₃—S(O)₂—).

If applicable, the above explanations with respect to alkyl groups applycorrespondingly to divalent alkyl groups (alkanediyl groups) includingthe divalent alkyl groups C_(u)H_(2u) and C_(v)H_(2v), which groups canalso be regarded as the alkyl part of a substituted alkyl group. Thus,divalent alkyl groups including the divalent alkyl groups C_(u)H_(2u)and C_(v)H_(2v) can also be straight-chain or branched, the bonds to theadjacent groups can be present in any positions and can start from thesame carbon atom or from different carbon atoms, and they can besubstituted by fluorine. Examples of divalent alkyl groups are —CH₂—,—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₃)—CH₂—,—CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂— and —CH₂—C(CH₃)₂—. Examples offluoro-substituted divalent alkyl groups which can contain 1 2, 3, 4, 5or 6 fluorine atoms, for example, are —CHF—, —CF₂—, —CF₂—CH₂—,—CH₂—CF₂—, —CF₂—CF₂—, —CF(CH₃)—, —C(CF₃)₂—, —C(CH₃)₂—CF₂— and—CF₂—C(CH₃)₂—. If the number u in a divalent alkyl group C_(u)H_(2u) orthe number v in a divalent alkyl group C_(v)H_(2v) is 0 (zero), the twoadjacent groups which are bonded to this group are directly bonded toone another through a single bond. For example, if the group R⁴⁰ is thegroup (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, which group is bonded to theremainder of the molecule via the C_(v)H_(2v) moiety as is symbolized bythe terminal line (hyphen) next to the C_(v)H_(2v) moiety representingthe free bond, and the number v therein is 0, the (C₃-C₇)-cycloalkylgroup is bonded directly through a single bond to the carbon atom whichcarries the group R⁴⁰. In one embodiment of the invention the number vis chosen from 0 and 1, wherein all numbers v are independent of eachother and can be identical or different.

The number of ring carbon atoms in a cycloalkyl group can be 3, 4, 5, 6or 7. The number of ring carbon atoms in a cycloalkenyl group can be 5,6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, examples of cycloalkenyl are cyclopentenyl,cyclohexenyl and cycloheptenyl. The double bond in a cycloalkenyl groupcan be present in any position with respect to the carbon atom inposition 1 via which the group is bonded to the indole ring, andcycloalkenyl can thus be cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,for example. In preferred embodiments of the present invention, acycloalkyl group, such as (C₃-C₇)-cycloalkyl, in the definition of anygroup is chosen from a subgroup of any two or more of the said specificcycloalkyl groups, for example from cyclopropyl and cyclobutyl, or fromcyclopropyl, cyclobutyl and cyclopentyl, or from cyclopropyl,cyclopentyl and cyclohexyl, or from cyclopentyl and cyclohexyl, or fromcyclopentyl, cyclohexyl and cycloheptyl. Similarly, in preferredembodiments a cycloalkenyl group is chosen from a subgroup of any two ormore of the said specific cycloalkenyl groups, for example fromcyclopentenyl and cyclohexenyl, or from cyclohexenyl and cycloheptenyl,or from cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl,cyclohex-2-enyl, cyclohept-1-enyl and cyclohept-2-enyl, or fromcyclopent-2-enyl, cyclopent-3-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-2-enyl, cyclohept-3-enyl and cyclohept-4-enyl, or fromcyclopent-2-enyl and cyclohex-2-enyl, or from cyclopent-2-enyl,cyclohex-2-enyl and cyclohept-2-enyl. In one embodiment of theinvention, the carbon atom via which the cycloalkenyl group representingR³⁰ is bonded to the indole ring, is not part of the double bond, i.e.,the cycloalkenyl group is not a cycloalk-1-enyl group. Cycloalkyl groupsand cycloalkenyl groups generally are optionally substituted by one ormore (C₁-C₄)-alkyl substituents. I.e., they are unsubstituted, i.e. donot carry alkyl substituents, or substituted, for example by 1, 2, 3 or4 identical or different (C₁-C₄)-alkyl substituents, for example bymethyl groups and/or ethyl groups and/or isopropyl groups and/ortert-butyl groups, in particular by methyl groups, which substituentscan be present in any positions. Examples of alkyl-substitutedcycloalkyl groups are 1-methyl-cyclopropyl, 2,2-dimethyl-cyclopropyl,1-methyl-cyclopentyl, 2,3-dimethyl-cyclopentyl, 1-methyl-cyclohexyl,4-methyl-cyclohexyl, 4-isopropyl-cyclohexyl, 4-tert-butyl-cyclohexyl and3,3,5,5-tetramethyl-cyclohexyl. Examples of alkyl-substitutedcycloalkenyl groups are 1-methyl-cyclopent-2-enyl,2-methyl-cyclopent-2-enyl, 3-methyl-cyclopent-2-enyl,3,4-dimethyl-cyclopent-3-enyl, 1-methyl-cyclohex-2-enyl,2-methyl-cyclohex-2-enyl, 3-methyl-cyclohex-2-enyl,4-methyl-cyclohex-2-enyl, 2-methyl-cyclohex-3-enyl,3-methyl-cyclohex-3-enyl, 4-methyl-cyclohex-3-enyl,2,3-dimethyl-cyclohex-2-enyl, 4,4-dimethyl-cyclohex-2-enyl,3,4-dimethyl-cyclohex-3-enyl. Cycloalkyl groups and cycloalkenyl groupsgenerally also are optionally substituted by one or more fluorine atoms.I.e., they are unsubstituted, i.e. do not carry fluorine atoms, orsubstituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorineatoms, preferably by 1, 2, 3, 4, 5 or 6 fluorine atoms. Cycloalkylgroups and cycloalkenyl groups can also be substituted simultaneously byfluorine and alkyl. The fluorine atoms can be present in any positionsand can also be present in an alkyl substituent. Examples offluoro-substituted cycloalkyl groups are 1-fluoro-cyclopropyl,2,2-difluoro-cyclopropyl, 3,3-difluoro-cyclobutyl, 1-fluoro-cyclohexyl,4,4-difluoro-cyclohexyl and 3,3,4,4,5,5-hexafluoro-cyclohexyl. Examplesof fluoro-substituted cycloalkenyl groups are 1-fluoro-cyclopent-2-enyl,1-fluoro-cyclohex-2-enyl, 4-fluoro-cyclohex-2-enyl,4,4-difluoro-cyclohex-2-enyl. In one embodiment of the invention,cycloalkyl groups are not optionally substituted by substituents chosenfrom fluorine and (C₁-C₄)-alkyl. If a cycloalkyl group or cycloalkenylgroup can be substituted by further substituents like hydroxy, as in thecase of a cycloalkyl group or cycloalkenyl group representing R³⁰, itcan be substituted by one or more such further substituents like hydroxyonly and not by substituents chosen from fluorine and (C₁-C₄)-alkyl, orby one or more such further substituents and simultaneously by one ormore substituents chosen from fluorine and (C₁-C₄)-alkyl. The number ofsuch further substituents like hydroxy which can be present on acycloalkyl or cycloalkenyl group, preferably is 1, 2 or 3, morepreferably 1 or 2, for example 1. The total number of all substituentsin a cycloalkyl group or cycloalkenyl group preferably is 1, 2, 3, 4, 5,6, 7 or 8, more preferably 1, 2, 3, 4 or 5, for example 1, 2 or 3. Suchfurther substituents like hydroxy can be present in any positions,provided that the resulting compound is sufficiently stable and issuitable as a subgroup in a pharmaceutical active compound. Preferably,a hydroxy substituent is not present in position 1 of a cycloalkenylgroup or cycloalkyl group representing R³⁰, and in a cycloalkenyl groupa hydroxy substituent is not present on a carbon atom which is part ofthe double bond. Examples of hydroxy-substituted cycloalkyl groups are3-hydroxy-cyclobutyl, 2-hydroxy-cyclopentyl, 3-hydroxy-cyclopentyl,3,4-dihydroxy-cyclopentyl, 2-hydroxy-cyclohexyl, 3-hydroxy-cyclohexyl,4-hydroxy-cyclohexyl, 2,3-dihydroxy-cyclohexyl,2,4-dihydroxy-cyclohexyl, 3,4-dihydroxy-cyclohexyl,3,5-dihydroxy-cyclohexyl, 3,4,5-trihydroxy-cyclohexyl,2-hydroxy-cycloheptyl, 3-hydroxy-cycloheptyl, 4-hydroxy-cycloheptyl.Examples of hydroxy-substituted cycloalkenyl groups are5-hydroxy-cyclopent-2-enyl, 4-hydroxy-cyclohex-2-enyl,5-hydroxy-cyclohex-2-enyl, 6-hydroxy-cyclohex-2-enyl,6-hydroxy-cyclohex-3-enyl. Examples of the group cycloalkylalkyl-, whichcan be present in the group (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, arecyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-,cyclohexylmethyl-, cycloheptylmethyl-, cyclopropyldifluoromethyl-,cyclobutyldifluoromethyl-, cyclopentyldifluoromethyl-,cyclohexyldifluoromethyl-, cycloheptyldifluoromethyl-,1-cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-,2-cyclobutylethyl-, 1-cyclopentylethyl-, 2-cyclopentylethyl-,1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-cycloheptylethyl-,2-cycloheptylethyl-.

A tetrahydropyranyl group representing R³⁰, which group can also bedesignated as oxanyl group or tetrahydro-2H-pyranyl group, can be bondedvia any carbon atom and can be tetrahydropyran-2-yl,tetrahydropyran-3-yl or tetrahydropyran-4-yl. Preferably,tetrahydropyranyl is tetrahydropyran-3-yl or tetrahydropyran-4-yl. Inone embodiment of the invention, tetrahydropyranyl istetrahydropyran-4-yl.

In substituted phenyl groups, the substituents can be present in anypositions. In monosubstituted phenyl groups, the substituent can bepresent in the 2-position, the 3-position or the 4-position. Indisubstituted phenyl groups, the substituents can be present in2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or3,5-position. In trisubstituted phenyl groups, the substituents can bepresent in 2,3,4-position, 2,3,5-position, 2,3,6-position,2,4,5-position, 2,4,6-position or 3,4,5-position. If a phenyl groupcarries four substituents, of which one, two, three or four substituentscan be fluorine atoms, for example, the unsubstituted ring carbon atomcan be present in the 2-position, the 3-position or the 4-position. If apolysubstituted phenyl group or heteroaryl group carries differentsubstituents, each substituent can be present in any suitable position,and the present invention comprises all positional isomers. The numberof substituents in a substituted phenyl group can be 1, 2, 3, 4 or 5.Preferably, a substituted phenyl group, and likewise a substitutedheteroaryl group, carries 1, 2 or 3, in particular 1 or 2, identical ordifferent substituents. In preferred embodiments of the invention, thesubstituents in substituted phenyl and heteroaryl groups are chosen fromany subgroup of the substituents listed in the respective definition,for example by substituents chosen from halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S(O)_(m)—, or from halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and cyano, or from halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in the case of a phenyl group orheteroaryl group representing R²⁰, wherein all alkyl groups can beunsubstituted or substituted by one or more fluorine atoms and, as anexample of substituents containing fluorine-substituted alkyl, thesubstituents comprising the group CF₃ (trifluoromethyl) such as CF₃itself, CF₃—O— or CF₃—S— may be included in each list of substituents inaddition to substituents comprising unsubstituted alkyl.

In a heteroaryl group, which is a residue of an aromatic monocyclic,5-membered or 6-membered heterocyclic ring system, the ring heteroatomsindicated in the definition of the group can be present in anycombination and can be present in any suitable position, provided thatthe group is in line with its definition and the resulting compound ofthe formula I is stable and suitable as a pharmaceutical activecompound. The one of the ring nitrogen atoms specifically referred to inthe definition of the group heteroaryl which can carry a hydrogen atomor a substituent such as alkyl, is the ring nitrogen atom in a5-membered ring system such as pyrrole, pyrazole, imidazole or triazoleto which an exocyclic atom or group is bonded. Examples of ring systemsfrom which a heteroaryl group can be derived are pyrrole, furan,thiophene, imidazole, pyrazole, triazoles such as [1,2,3]triazole and[1,2,4]triazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole),thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), oxadiazoles suchas [1,2,4]oxadiazole, [1,3,4]oxadiazole and [1,2,5]oxadiazole,thiadiazoles such as [1,3,4]thiadiazole, pyridine, pyridazine,pyrimidine, pyrazine, triazines such as [1,2,3]triazine, [1,2,4]triazineand [1,3,5]triazine. In one embodiment of the invention, a heteroarylgroup comprises one or two identical or different ring heteroatoms, inanother embodiment of the invention heteroaryl comprises one ringheteroatom, which are defined as indicated. In another embodimentheteroaryl is chosen from thiophenyl, thiazolyl and pyridinyl. Inanother embodiment heteroaryl is chosen from thiophenyl and pyridinyl.In another embodiment heteroaryl is thiophenyl. Heteroaryl groups can bebonded via any ring carbon atom. For example, a thiophenyl group(thienyl group) can be thiophen-2-yl (2-thienyl) or thiophen-3-yl(3-thienyl), furanyl can be furan-2-yl or furan-3-yl, pyridinyl(pyridyl) can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, pyrazolylcan be 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 2H-pyrazol-3-yl, imidazolylcan be 1H-imidazol-2-yl, 1H-imidazol-4-yl or 3H-imidazolyl-4-yl,thiazolyl can be thiazol-2-yl, thiazol-4-yl or thiazol-5-yl,[1,2,4]triazolyl can be 1H-[1,2,4]triazol-3-yl, 2H-[1,2,4]triazol-3-ylor 4H-[1,2,4]triazol-3-yl.

In substituted heteroaryl groups, the substituents can be present in anypositions, for example in a thiophen-2-yl group or a furan-2-yl group inthe 3-position and/or in the 4-position and/or in the 5-position, in athiophen-3-yl group or a furan-3-yl group in the 2-position and/or inthe 4-position and/or in the 5-position, in a pyridin-2-yl group in the3-position and/or in the 4-position and/or in the 5-position and/or inthe 6-position, in a pyridin-3-yl group in the 2-position and/or in the4-position and/or in the 5-position and/or in the 6-position, in apyridin-4-yl group in the 2-position and/or in the 3-position and/or inthe 5-position and/or in the 6-position. Preferably, a substitutedheteroaryl group is substituted by one, two or three, in particular oneor two, for example one, identical or different substituents. If a ringnitrogen atom is present which can carry a hydrogen atom or asubstituent, the substituent on this nitrogen atom can be a methylgroup, an ethyl group, a propyl group or a tert-butyl group, forexample, which groups can also be monosubstituted or polysubstituted byfluorine. Generally, suitable ring nitrogen atoms in an aromatic ring ofa heteroaryl group, for example the nitrogen atom in a pyridinyl groupor a nitrogen atom in a [1,2,5]oxadiazolyl group, can also carry anoxido substituent —O⁻ and compounds of the formula I thus be present inthe form of an N-oxide.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine,chlorine or bromine, in particular fluorine or chlorine.

The present invention comprises all stereoisomeric forms of thecompounds of the formula I, for example, all possible enantiomers anddiastereomers including cis/trans isomers. The invention likewisecomprises mixtures of two or more stereoisomeric forms, for examplemixtures of enantiomers and/or diastereomers including cis/transisomers, in all ratios. Asymmetric centers contained in the compounds ofthe formula I, for example in unsubstituted or substituted alkyl groupsor in the diazacycloalkane ring depicted in formula I, can allindependently of one another have the S configuration or the Rconfiguration. The invention relates to enantiomers, both thelevorotatory and the dextrorotatory antipode, in enantiomerically pureform and substantially enantiomerically pure form and in the form ofracemates and in the form of mixtures of the two enantiomers in allratios. The invention likewise relates to diastereomers in the form ofpure and substantially pure diastereomers and in the form of mixtures oftwo or more diastereomers in all ratios. The invention also comprisesall cis/trans isomers of the compounds of the formula I in pure form andsubstantially pure form and in the form of mixtures of the cis isomerand the trans isomer in all ratios. Cis/trans isomerism can occur insubstituted cycloalkane rings and in the diazacycloalkane ring depictedin formula I, for example. The preparation of individual stereoisomers,if desired, can be carried out by resolution of a mixture according tocustomary methods, for example by chromatography or crystallization, orby use of stereochemically uniform starting compounds in the synthesisor by stereoselective reactions. Optionally, before a separation ofstereoisomers a derivatization can be carried out. The separation of amixture of stereoisomers can be carried out at the stage of the compoundof the formula I or at the stage of an intermediate in the course of thesynthesis. The invention also comprises all tautomeric forms of thecompounds of the formula I.

Physiologically acceptable salts of the compounds of the formula I arein particular salts with a nontoxic salt component and preferably arepharmaceutically utilizable salts. They can contain inorganic or organicsalt components. Such salts can be formed, for example, from compoundsof the formula I which contain an acidic group, for example a carboxylicacid group (HO—CO—) or a sulfonic acid group (HO—S(O)₂—) and nontoxicinorganic or organic bases. Suitable bases are, for example, alkalimetal compounds or alkaline earth metal compounds, such as sodiumhydroxide, potassium hydroxide, sodium carbonate or sodiumhydrogencarbonate, or ammonia, organic amino compounds and quaternaryammonium hydroxides. Reactions of compounds of the formula I with basesfor the preparation of the salts are in general carried out according tocustomary procedures in a solvent or diluent. On account of thephysiological and chemical stability, advantageous salts of acidicgroups are in many cases sodium, potassium, magnesium or calcium saltsor ammonium salts which can also carry one or more organic groups on thenitrogen atom. Compounds of the formula I which contain a basic, i.e.protonatable, group, for example an amino group, the diazacycloalkanemoiety depicted in formula I in case R¹⁰ is hydrogen, or another basicheterocycle, can be present in the form of their acid addition saltswith physiologically acceptable acids, for example as salt with hydrogenchloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid,benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which ingeneral can be prepared from the compounds of the formula I by reactionwith an acid in a solvent or diluent according to customary procedures.As usual, in particular in the case of acid addition salts of a compoundcontaining two or more basic groups, in an obtained salt the ratio ofthe salt components can deviate upward or downward from thestoichiometric ratio, such as the molar ratio 1:1 or 1:2 in the case ofthe acid addition salt of a compound of the formula I containing one ortwo basic groups with a monovalent acid, and vary depending on theapplied conditions. The present invention comprises also saltscontaining the components in a non-stoichiometric ratio, and anindication that an acid addition salt of a compound of the formula Icontains an acid in equimolar amount, for example, also allows for alower or higher amount of acid in the obtained salt, for example about0.8 or about 1.1 mol of acid per mol of compound of the formula I. Ifthe compounds of the formula I simultaneously contain an acidic and abasic group in the molecule, the invention also includes internal salts(betaines, zwitterions) in addition to the salt forms mentioned. Thepresent invention also comprises all salts of the compounds of theformula I which, because of low physiological tolerability, are notdirectly suitable for use as a pharmaceutical, but are suitable asintermediates for chemical reactions or for the preparation ofphysiologically acceptable salts, for example by means of anion exchangeor cation exchange. A subject of the present invention also are solvatesof the compounds of the formula I and their salts, such as hydrates andadducts with alcohols like (C₁-C₄)-alkanols, in particularphysiologically acceptable solvates, as well as active metabolites ofcompounds of the formula I and prodrugs of the compounds of the formulaI, i.e. compounds which in vitro may not necessarily exhibitpharmacological activity but which in vivo are converted intopharmacologically active compounds of the formula I, for examplecompounds which are converted by metabolic hydrolysis into compounds ofthe formula I. Examples of such prodrugs are compounds in which anacylatable nitrogen atom, for example the nitrogen atom carrying thegroup R¹⁰ in the diazacycloalkane moiety depicted in formula I in caseR¹⁰ is hydrogen, carries an alkyl-O—CO— group or an acyl group such asan alkyl-CO— group, for example, and thus has been converted into acarbamate group or an amide group, or compounds in which a carboxylicacid group has been esterified.

The group A is preferably chosen from O, S, NCH₃ and C(R^(a))₂, morepreferably from O, S and C(R^(a))₂, particularly preferably from O andC(R^(a))₂. In one embodiment of the invention the group A is chosen fromO and S. In another embodiment of the invention the group A is O, inanother embodiment the group A is C(R^(a))₂.

If the two groups R^(a) together are a divalent (C₂-C₈)-alkyl group, thesaid alkyl group is preferably bonded to the carbon atom carrying thegroups R^(a) via two distinct carbon atoms and forms, together with thecarbon atom carrying the groups R^(a), a cycloalkane ring to which theindole ring depicted in formula I and the group R²⁰ are bonded in thesame ring position. The said cycloalkane ring, like a cycloalkane ringin the compounds of the formula I in general, can carry one or more(C₁-C₄)-alkyl groups, for example one, two, three or four methyl groups,and/or one or more, for example one, two, three or four fluorine atoms.Preferably the said cycloalkane ring is a cyclopropane, cyclobutane,cyclopentane or cyclohexane ring which can all be unsubstituted orsubstituted by alkyl and/or fluorine as indicated. In one embodiment ofthe invention the said cycloalkane ring is a cyclopropane ring which canbe unsubstituted or substituted by alkyl and/or fluorine as indicated,i.e., in this embodiment the divalent (C₂-C₈)-alkyl group is anethane-1,2-diyl group (1,2-ethylene group) which is unsubstituted orsubstituted by alkyl and/or fluorine as indicated. Preferably thedivalent (C₂-C₈)-alkyl group is a (C₂-C₅)-alkyl group, more preferably a(C₂-C₄)-alkyl group, for example a C₂-alkyl group. In one embodiment ofthe invention, the groups R^(a) are chosen from hydrogen and fluorine,in another embodiment from hydrogen and (C₁-C₄)-alkyl, wherein the twogroups R^(a) are independent of each other and can be identical ordifferent, or in all these embodiments the two groups R^(a) together area divalent (C₂-C₈)-alkyl group. In one embodiment of the invention thegroups R^(a) are identical or different groups chosen from hydrogen andfluorine, in another embodiment they are identical and different groupschosen from hydrogen and (C₁-C₄)-alkyl. In another embodiment of theinvention the groups R^(a) are identical and chosen from hydrogen,fluorine and (C₁-C₄)-alkyl, or the two groups R^(a) together are adivalent (C₂-C₈)-alkyl group. In another embodiment of the invention thegroups R^(a) both are hydrogen or the two groups R^(a) together are adivalent (C₂-C₈)-alkyl group. In a further embodiment of the invention,the groups R^(a) both are hydrogen, i.e. the group C(R^(a))₂representing the group A is the group CH₂. A (C₁-C₄)-alkyl grouprepresenting R^(a) preferably is methyl.

In the diazacycloalkane moiety depicted in formula I, preferably one,two, three or four, more preferably one, two or three, particularlypreferably one or two, for example one, of the groups R, which areindependent of each other and can be identical or different, are definedas above or below and are chosen from all denotations comprised by thedefinition including hydrogen, and all other groups R are hydrogen. Inone embodiment of the invention, all groups R are hydrogen and thediazacycloalkane moiety depicted in formula I is a piperazine ring,homopiperazine ring or 1,5-diazocane ring, in particular a piperazinering, which carries the group R¹⁰ but is not substituted by substituentson ring carbon atoms. Groups R which are different from hydrogen can bepresent in any positions of the diazacycloalkane moiety provided thatthe resulting compound of the formula I is stable and suitable as asubgroup in a pharmaceutical active compound. In one embodiment of theinvention (C₁-C₄)-alkyl-O— groups representing R are not bonded tocarbon atoms in the diazacycloalkane ring depicted in formula I whichare adjacent to a ring nitrogen atom. Preferably only one or two, forexample only one, of the groups R are (C₁-C₄)-alkyl-O—.

In one embodiment of the invention the groups R are chosen fromhydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— and R¹—NH—CO—C_(u)H_(2u)—, in anotherembodiment from hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl- and R¹—NH—CO—C_(u)H_(2u)—, in another embodimentfrom hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andR¹—NH—CO—C_(u)H_(2u)—, in another embodiment from hydrogen,(C₁-C₄)-alkyl and hydroxy-(C₁-C₄)-alkyl-, in another embodiment fromhydrogen, (C₁-C₄)-alkyl and R¹—NH—C_(u)H_(2u)—, in another embodimentfrom hydrogen and (C₁-C₄)-alkyl, in another embodiment from hydrogen andR¹—NH—CO—C_(u)H_(2u)—, wherein all groups R are independent of eachother and can be identical or different and phenyl is optionallysubstituted as indicated. In one embodiment of the invention one of thegroups R is chosen from (C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— andR¹—NH—CO—C_(u)H_(2u)— and in particular is R¹—NH—CO—C_(u)H_(2u)—, andall other groups R are hydrogen. Groups R which are different fromhydrogen, can be bonded to any ring carbon atoms in the diazacycloalkanering depicted in formula I. In case two or more groups R are presentwhich are different from hydrogen, a ring carbon atom can carry eitherone or two such groups R which are different from hydrogen. In case thediazacycloalkane ring depicted in formula I is a piperazine ringcarrying one group R which is different from hydrogen, this group R canbe present in the 2-position or the 3-position with respect to the ringnitrogen atom which is bonded to the CO group depicted in formula I. Incase the diazacycloalkane ring depicted in formula I is a piperazinering carrying two groups R which are different from hydrogen, thesegroups R can both be present in the 2-position, or they can both bepresent in the 3-position, or they can be present in positions 2 and 3,or in positions 2 and 5, or in positions 2 and 6, or in positions 3 and5, with respect to the ring nitrogen atom which is bonded to the COgroup depicted in formula I, where in case of two different groups Reach of them can be present in each position. In one embodiment of theinvention the number u is chosen from 0 and 1, in another embodiment uis chosen from 1 and 2, in another embodiment u is 0, in anotherembodiment u is 1, in another embodiment u is 2, wherein all numbers uare independent of each other and can be identical or different.

In one embodiment of the invention R¹ is chosen from (C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl- and H₂N—CO—(C₁-C₄)-alkyl-, in another embodimentfrom (C₁-C₄)-alkyl and hydroxy-(C₁-C₄)-alkyl-, in another embodimentfrom (C₁-C₄)-alkyl and H₂N—CO—(C₁-C₄)-alkyl-. In one embodiment of theinvention R¹ is hydrogen, in another embodiment R¹ is (C₁-C₄)-alkyl, inanother embodiment R¹ is hydroxy-(C₁-C₄)-alkyl-, in another embodimentR¹ is H₂N—CO—(C₁-C₄)-alkyl-.

R¹⁰ is preferably chosen from hydrogen and (C₁-C₆)-alkyl-O—CO—, morepreferably from hydrogen and (C₁-C₄)-alkyl-O—CO—. In one embodiment ofthe invention, R¹⁰ is hydrogen.

In one embodiment of the invention, R²⁰ is chosen from phenyl andheteroaryl wherein heteroaryl is chosen from thiophenyl, thiazolyl andpyridinyl, in another embodiment from phenyl and heteroaryl whereinheteroaryl is thiophenyl, which are all optionally substituted asindicated. In another embodiment of the invention, R²⁰ is phenyl whichis optionally substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, hydroxy and cyano. Preferably the number ofsubstituents in a substituted group R²⁰ is one, two, three or four, morepreferably one, two or three, for example one or two. The substituentsin a substituted group R²⁰ can be present on carbon atoms in anypositions as indicated above with respect to substituted phenyl andheteroaryl groups in general. Thus, for example, in the case of amonosubstituted phenyl group representing R²⁰, the substituent can bepresent in the 2-position, the 3-position or the 4-position, and in thecase of a disubstituted phenyl group the substituents can be present inpositions 2 and 3, or positions 2 and 4, or positions 2 and 5, orpositions 2 and 6, or positions 3 and 4, or positions 3 and 5. Likewise,a trisubstituted phenyl group representing R²⁰ can carry thesubstituents in any positions and can be a group such as3-chloro-2,6-dimethyl-phenyl, 3-fluoro-2,6-dimethyl-phenyl,6-chloro-3-fluoro-2-methyl-phenyl or 2-chloro-3-fluoro-6-methyl-phenyl,for example, in case of a phenyl group trisubstituted by fluorine and/orchlorine and methyl. The substituents which can be present in the groupR²⁰, are preferably chosen from halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)— and cyano, more preferablyfrom halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O— and(C₁-C₄)-alkyl-S(O)_(m)—, particularly preferably from halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, more particularly preferably fromhalogen and (C₁-C₄)-alkyl, for example from chlorine, fluorine andmethyl, wherein in one embodiment of the invention the alkyl groups insubstituents in the group R²⁰ can be unsubstituted or substituted by oneor more fluorine atoms and, as an example of substituents containingfluorine-substituted alkyl, the substituents comprising the grouptrifluoromethyl such as CF₃ itself, CF₃—O— or CF₃—S— may be included ineach list of substituents in addition to substituents comprisingunsubstituted alkyl, and in another embodiment of the invention thealkyl groups in substituents in the group R²⁰ are not substituted byfluorine and in this latter embodiment the said alkyl thus meansunsubstituted alkyl. Specific groups in addition to the afore-mentionedspecific groups, which can represent the group R²⁰ and from which, orfrom any subgroup of which, R²⁰ in the compounds of the formula I can bechosen, include phenyl, i.e. unsubstituted phenyl, 2-fluoro-phenyl,3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl,4-chloro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl),4-methyl-phenyl (p-tolyl), 2-ethyl-phenyl, 3-ethyl-phenyl,4-ethyl-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl,2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl,2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl,2,6-dichloro-phenyl, 3,4-dichloro-phenyl, 3,5-dichloro-phenyl,2-chloro-3-fluoro-phenyl, 2-chloro-4-fluoro-phenyl,2-chloro-5-fluoro-phenyl, 2-chloro-6-fluoro-phenyl,3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl,3-chloro-5-fluoro-phenyl, 4-chloro-2-fluoro-phenyl,4-chloro-3-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 2,3-dimethyl-phenyl,2,4-dimethyl-phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl,3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2-fluoro-3-methyl-phenyl,2-fluoro-4-methyl-phenyl, 2-fluoro-5-methyl-phenyl,2-fluoro-6-methyl-phenyl, 3-fluoro-2-methyl-phenyl,3-fluoro-4-methyl-phenyl, 3-fluoro-5-methyl-phenyl,4-fluoro-2-methyl-phenyl, 4-fluoro-3-methyl-phenyl,5-fluoro-2-methyl-phenyl, 2-chloro-3-methyl-phenyl,2-chloro-4-methyl-phenyl, 2-chloro-5-methyl-phenyl,2-chloro-6-methyl-phenyl, 3-chloro-2-methyl-phenyl,3-chloro-4-methyl-phenyl, 3-chloro-5-methyl-phenyl,4-chloro-2-methyl-phenyl, 4-chloro-3-methyl-phenyl,5-chloro-2-methyl-phenyl, 2-methoxy-3-methyl-phenyl,2-methoxy-4-methyl-phenyl, 2-methoxy-5-methyl-phenyl,2-methoxy-6-methyl-phenyl, 3-methoxy-2-methyl-phenyl,3-methoxy-4-methyl-phenyl, 3-methoxy-5-methyl-phenyl,4-methoxy-2-methyl-phenyl, 4-methoxy-3-methyl-phenyl,5-methoxy-2-methyl-phenyl, for example.

In one embodiment of the invention, R³⁰ is chosen from(C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, tetrahydropyranyl and phenyl,in another embodiment from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl andphenyl, in another embodiment from (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkenyl and tetrahydropyranyl, in another embodiment from(C₃-C₇)-cycloalkyl, (C₅-C₅)-cycloalkenyl, phenyl and heteroaryl, inanother embodiment from (C₃-C₇)-cycloalkyl, phenyl and heteroaryl, inanother embodiment from (C₃-C₇)-cycloalkyl and (C₅-C₇)-cycloalkenyl, inanother embodiment from (C₃-C₇)-cycloalkyl and phenyl, wherein thecycloalkyl, cycloalkenyl, phenyl and heteroaryl groups are alloptionally substituted as indicated and cycloalkyl preferably is(C₅-C₇)-cycloalkyl, more preferably (C₅-C₆)-cycloalkyl, for examplecyclohexyl, cycloalkenyl preferably is (C₅-C₆)-cycloalkenyl, for examplecyclohexenyl, and heteroaryl preferably is chosen from thiophenyl andpyridinyl. In another embodiment of the invention R³⁰ is phenyl which isoptionally substituted as indicated. Preferably the number ofsubstituents in a substituted group R³⁰ is one, two, three or four, morepreferably one, two or three, particularly preferably one or two, forexample one. The substituents in a substituted group R³⁰ can be presenton carbon atoms in any positions as indicated above with respect tosubstituted cycloalkyl, cycloalkenyl, phenyl and heteroaryl groups ingeneral. For example, in the case of a monosubstituted phenyl grouprepresenting R³⁰, the substituent can be present in the 2-position, the3-position or the 4-position, and in the case of a disubstituted phenylgroup the substituents can be present in positions 2 and 3, or positions2 and 4, or positions 2 and 5, or positions 2 and 6, or positions 3 and4, or positions 3 and 5. The substituents which can be present in acycloalkyl or cycloalkenyl group representing R³⁰ are preferably chosenfrom fluorine, methyl and hydroxy, for example from fluorine and methyl.In one embodiment of the invention, the substituents in a cycloalkyl orcycloalkenyl group representing R³⁰ are hydroxy. In another embodimentof the invention, a cycloalkyl or cycloalkenyl group representing R³⁰ isunsubstituted. The substituents which can be present in a phenyl orheteroaryl group representing R³⁰, are preferably chosen from halogen,(C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-,(C₁-C₄)-alkyl-CO—NH—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,hydroxy-(C₁-C₆)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-CO—NH—(C₁-C₄)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano,more preferably from halogen, (C₁-C₆)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano,particularly preferably from halogen, (C₁-C₆)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O— and(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, more particularly preferably fromhalogen, (C₁-C₆)-alkyl, hydroxy, (C₁-C₆)-alkyl-O— and(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, especially preferably from halogen,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl-O— and (C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—,for example from halogen, (C₁-C₆)-alkyl-O— and(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O— or from halogen, (C₁-C₆)-alkyl and(C₁-C₆)-alkyl-O— or from halogen and (C₁-C₄)-alkyl, wherein in oneembodiment of the invention the alkyl groups in substituents in phenyland heteroaryl groups representing R³⁰ can be unsubstituted orsubstituted by one or more fluorine atoms and, as an example ofsubstituents containing fluorine-substituted alkyl, the substituentscomprising the group trifluoromethyl such as CF₃ itself, CF₃—O— orCF₃—S— may be included in each list of substituents in addition tosubstituents comprising unsubstituted alkyl, and in another embodimentof the invention the alkyl groups in substituents in the group R³⁰ arenot substituted by fluorine and in this latter embodiment the said alkylthus means unsubstituted alkyl. In one embodiment of the invention, a(C₁-C₆)-alkyl group in a substituent in R³⁰ is a (C₁-C₄)-alkyl group. Inone embodiment of the invention, the substituents which can be presentin a phenyl or heteroaryl group representing R³⁰, are chosen fromhalogen, preferably from fluorine, chlorine and bromine, more preferablyfrom fluorine and chlorine. Specific groups which can occur as the groupR³⁰ and from which, or from any subgroup of which, R³⁰ in the compoundsof the formula I can be chosen, include cyclopentyl, cyclohexyl,cycloheptyl, cyclopent-2-enyl, cyclohex-2-enyl, cyclohept-2-enyl,4-fluoro-cyclohexyl, 4-methyl-cyclohexyl, 2-hydroxy-cyclopentyl,3-hydroxy-cyclopentyl, 2-hydroxy-cyclohexyl, 3-hydroxy-cyclohexyl,4-hydroxy-cyclohexyl, 2-hydroxy-cycloheptyl, 3-hydroxy-cycloheptyl,4-hydroxy-cycloheptyl, 4,4-difluoro-cyclohexyl, 3,3-dimethyl-cyclohexyl,4,4-dimethyl-cyclohexyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,phenyl, i.e. unsubstituted phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl,4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl,3-bromo-phenyl, 4-bromo-phenyl, 2-methyl-phenyl, 3-methyl-phenyl,4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl,2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl,2-(2-methoxyethoxy)-phenyl, 3-(2-methoxyethoxy)-phenyl,4-(2-methoxyethoxy)-phenyl, 2-(3-methoxypropoxy)-phenyl,3-(3-methoxypropoxy)-phenyl, 4-(3-methoxypropoxy)-phenyl, thiophen-2-yl,thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-hydroxypyridin-3-yl, 4-hydroxypyridin-3-yl, 5-hydroxy-pyridin-3-yl,6-hydroxy-pyridin-3-yl, 2-methoxy-pyridin-3-yl, 4-methoxy-pyridin-3-yl,5-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-hydroxy-pyridin-4-yl,3-hydroxy-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methoxy-pyridin-4-yl,for example.

The substituents R⁴⁰ can be present in any of positions 4 and/or 5and/or 6 and/or 7 in the 6-membered ring of the indole ring depicted informula I. In case the number n of the substituents R⁴⁰ is less than 4,all carbon atoms in positions 4, 5, 6 and 7 of the indole ring which donot carry a substituent R⁴⁰ carry a hydrogen atom, i.e. the respectivering members are CH groups. In case the number n is 0, all ring carbonatoms in positions 4, 5, 6 and 7 of the indole ring carry hydrogenatoms. Preferably, the number n of the substituents R⁴⁰ is chosen from0, 1, 2 and 3, more preferably from 0, 1 and 2, for example from 0and 1. In one embodiment of the invention the number n is 2. In anotherembodiment the number n is 1. In another embodiment the number n is 0,i.e. no substituent R⁴⁰ is present in the compound of the formula I. R⁴⁰is preferably chosen from halogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl-,hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy,(C₁-C₄)-alkyl-O—, hydroxy-(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, phenyl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-CO—O—,(C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-S(O)_(m)—, HO—CO—,(C₁-C₄)-alkyl-O—CO—, H₂N—CO— and cyano, more preferably from halogen,(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,hydroxy, (C₁-C₄)-alkyl-O—, hydroxy-(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, phenyl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-CO—O—,(C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-S(O)_(m)—, HO—CO—,(C₁-C₄)-alkyl-O—CO—, H₂N—CO— and cyano, particularly preferably fromhalogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, HO—CO—, (C₁-C₄)-alkyl-O—CO—and H₂N—CO—, more particularly preferably from halogen, (C₁-C₄)-alkyl,hydroxy, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-O—CO— andH₂N—CO—, especially preferably from halogen, (C₁-C₄)-alkyl, hydroxy,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—CO—and H₂N—CO—, wherein all substituents R⁴⁰ are independent of each otherand can be identical or different, and wherein all phenyl groups areindependently of each other optionally substituted as indicated. In oneembodiment of the invention, R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl,hydroxy, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-O—CO—,HO—CO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O— and H₂N—CO—,preferably from halogen, (C₁-C₄)-alkyl, hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—CO— and H₂N—CO—, forexample from halogen, (C₁-C₄)-alkyl, hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO— and H₂N—CO— or from halogen, (C₁-C₄)-alkyl, hydroxy,(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— or from halogen,(C₁-C₄)-alkyl, hydroxy and (C₁-C₄)-alkyl-O—, wherein all substituentsR⁴⁰ are independent of each other and can be identical or different.Preferably, not more than two of the substituents R⁴⁰ are NO₂. In oneembodiment of the invention, the number n is chosen from 1, 2, 3 and 4,preferably from 1, 2 and 3, more preferably from 1 and 2, and can be 1,for example. I.e., in this latter embodiment at least one substituentR⁴⁰ is present in the compounds of the formula I, preferably one, two orthree substituents R⁴⁰, more preferably one or two substituents R⁴⁰, forexample one substituent R⁴⁰.

In one embodiment of the invention at least one substituent R⁴⁰ whichcan be present in the compounds of the formula I, preferably one or twosubstituents R⁴⁰, for example one substituent R⁴⁰, is a substituentwherein the atom within the substituent via which it is bonded to thecarbon atom in the 6-membered ring of the indole moiety, is an oxygenatom, i.e., it is chosen from hydroxy, (C₁-C₄)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—, phenyl-(C₁-C₄)-alkyl-O—,heteroaryl-(C₁-C₄)-alkyl-O—, hydroxy-(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, heteroaryl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—, H₂N—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—CO—O—,(C₁-C₄)-alkyl-NH—CO—O— and (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—NH—CO—O—,wherein such substituents are independent of each other and can beidentical or different and wherein all phenyl and heteroaryl groups canindependently of each other be substituted as indicated. Preferably,such substituents are chosen from hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O— and (C₁-C₄)-alkyl-NH—CO—O—, and more preferably fromhydroxy, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O— and(C₁-C₄)-alkyl-CO—O—, particularly preferably from hydroxy,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O— and di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, moreparticularly preferably are chosen from hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— and phenyl-O—(C₁-C₄)-alkyl-O—,especially preferably from hydroxy, (C₁-C₄)-alkyl-O— and(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, more especially preferably fromhydroxy and (C₁-C₄)-alkoxy. In one embodiment, such substituents arechosen from hydroxy, (C₁-C₄)-alkyl-O—, hydroxy-(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, phenyl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—, H₂N—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O— and (C₁-C₄)-alkyl-NH—CO—O—, preferably from hydroxy,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O— and H₂N—CO—(C₁-C₄)-alkyl-O—, morepreferably from hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,HO—CO—(C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—,particularly preferably from hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O— anddi((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, more particularly preferably fromhydroxy, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,especially preferably from preferably from hydroxy and (C₁-C₄)-alkyl-O—,wherein such substituents are independent of each other and can beidentical or different. If besides such substituents bonded via anoxygen atom further substituents R⁴⁰ are present in a compound of theformula I, they are chosen from all other meanings of R⁴⁰ listed above,and preferably are chosen from halogen and (C₁-C₄)-alkyl, wherein allsuch further substituents are independent of each other and can beidentical or different. In one embodiment, one such substituent R⁴⁰bonded via an oxygen atom is present in position 5 or in position 6 ofthe indole ring. In another embodiment two identical or different suchsubstituents are present in positions 5 and 6 of the indole ring.

In a compound of the formula I which contains one substituent R⁴⁰, thesubstituent can be present in position 4 or position 5 or position 6 orposition 7 of the indole ring. In a compound of the formula I whichcontains two substituents R⁴⁰, the substituents can be present inpositions 4 and 5 or positions 4 and 6 or positions 4 and 7 or positions5 and 6 or positions 5 and 7 or positions 6 and 7 of the indole ring. Ina compound of the formula I which contains three substituents R⁴⁰, thesubstituents can be present in positions 4, 5 and 6 or in positions 4, 5and 7 or in positions 4, 6 and 7 or in positions 5, 6 and 7. In oneembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 4 or position 5 or in positions 4 and 5 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms. In anotherembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 4 or position 6 or in positions 4 and 6 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms. In anotherembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 4 or position 7 or in positions 4 and 7 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms. In anotherembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 5 or position 6 or in positions 5 and 6 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms. In anotherembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 5 or position 7 or in positions 5 and 7 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms. In anotherembodiment of the invention, the compounds of the formula I containzero, one or two substituents R⁴⁰ wherein the substituents R⁴⁰ arepresent in position 6 or position 7 or in positions 6 and 7 and theother of positions 4, 5, 6 and 7 carry hydrogen atoms.

In one embodiment of the invention the number p is 2 and the number q ischosen from 2 and 3. In another embodiment of the invention both p and qare 2, i.e., the diazacycloalkane ring depicted in formula I is apiperazine ring and the compound of the formula I is a compound of theformula Ia. In another embodiment of the invention p is 2 and q is 3,i.e., the diazacycloalkane ring depicted in formula I is ahomopiperazine ring and the compound of the formula I is a compound ofthe formula Ib. In another embodiment of the invention both p and q are3, i.e., the diazacycloalkane ring depicted in formula I is a1,5-diazocane ring and the compound of the formula I is a compound ofthe formula Ic. A, R, R¹⁰, R²⁰, R³⁰, R⁴⁰ and n in the formulae Ia, Iband Ic are defined as in formula I.

In preferred compounds of the invention any one or more structuralelements such as groups, substituents and numbers are defined as in anyof the preferred definitions of the elements or in any specifiedembodiment and/or can have one or more of the specific meanings whichare mentioned as examples of elements, wherein all combinations of oneor more preferred definitions and embodiments and/or specific meaningsare a subject of the present invention. Also with respect to allpreferred compounds of the formula I, all their stereoisomeric forms andmixtures of stereoisomeric forms in all ratios, and theirphysiologically acceptable salts, and the physiologically acceptablesolvates of any of them, are a subject of the present invention.Similarly, also with respect to all specific compounds disclosed herein,such as the example compounds, which represent embodiments of theinvention wherein the various groups and numbers in the generaldefinition of the compounds of the formula I have the specific meaningspresent in the respective specific compound, all their stereoisomericforms and mixtures of stereoisomeric forms in all ratios, and theirphysiologically acceptable salts, and the physiologically acceptablesolvates of any of them, are a subject of the present invention. Inparticular, a subject of the invention are all specific compoundsdisclosed herein, independently thereof whether they are disclosed as afree compound and/or as a specific salt, both in the form of the freecompound and in the form of all its physiologically acceptable salts,and if a specific salt is disclosed, additionally in the form of thisspecific salt, and the physiologically acceptable solvates thereof.

As an example of compounds of the invention in which any one or morestructural elements are defined as in preferred definitions, compoundsof the formula I may be mentioned wherein p and q are both 2, R¹⁰ ishydrogen and A is chosen from O and C(R^(a))₂, i.e. the compounds of theformula Ia wherein R¹⁰ is hydrogen and A is chosen from O and C(R^(a))₂,and all other groups and numbers are defined as in the generaldefinition of the compounds of the formula I or in any of the preferreddefinitions or embodiments of the invention, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and the physiologically acceptable salts thereof, and thephysiologically acceptable solvates of any of them.

Another such example are compounds of the formula I, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and the physiologically acceptable salts thereof, and thephysiologically acceptable solvates of any of them, wherein

A is chosen from O, S, NCH₃ and C(R^(a))₂;R^(a) is chosen from hydrogen, fluorine and methyl, wherein the twogroups R^(a) are independent of each other and can be identical ordifferent, or the two groups R^(a) together are a divalent (C₂-C₅)-alkylgroup;R is chosen from hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— and R¹—NH—CO—C_(u)H_(2u)—, wherein allgroups R are independent of each other and can be identical ordifferent;R¹ is chosen from (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andH₂N—CO—(C₁-C₄)-alkyl-;R¹⁰ is chosen from hydrogen, (C₁-C₆)-alkyl-O—CO— and(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—;R²⁰ is chosen from phenyl and heteroaryl, which are optionallysubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—,hydroxy and cyano;R³⁰ is chosen from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,tetrahydropyranyl, phenyl and heteroaryl, wherein cycloalkyl andcycloalkenyl are optionally substituted by one or more identical ordifferent substituents chosen from fluorine, (C₁-C₄)-alkyl and hydroxy,and phenyl and heteroaryl are optionally substituted by one or moreidentical or different substituents chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano;R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-S(O)_(m)—,HO—CO—, (C₁-C₄)-alkyl-O—CO—, H₂N—CO— and cyano, wherein all substituentsR⁴⁰ are independent of each other and can be identical or different;heteroaryl is chosen from thiophenyl and pyridinyl;m is chosen from 0, 1 and 2, wherein all numbers m are independent ofeach other and can be identical or different;n is chosen from 0, 1, 2 and 3;p is 2 and q is chosen from 2 and 3;u is chosen from 0, 1 and 2, wherein all numbers u are independent ofeach other and can be identical or different;v is chosen from 0, 1 and 2;wherein all alkyl groups, independently of each other, are optionallysubstituted by one or more fluorine atoms;wherein the cycloalkyl group is optionally substituted by one or moreidentical or different substituents chosen from flourine and(C₁-C₄)-alkyl, unless specified otherwise;wherein all phenyl groups present in R and R⁴⁰, independently of eachother, are optionally substituted by one or more identical of differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)₂— and cyano.

Another such example are compounds of the formula I, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and the physiologically acceptable salts thereof, and thephysiologically acceptable solvates of any of them, wherein

A is chosen from O, S and C(R^(a))₂;R^(a) is chosen from hydrogen, fluorine and methyl, wherein the twogroups R^(a) are independent of each other and can be identical ordifferent, or the two groups R^(a) together are a divalent (C₂-C₅)-alkylgroup;R is chosen from hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, phenyl-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— and R¹—NH—CO—C_(u)H_(2u)—, wherein allgroups R are independent of each other and can be identical ordifferent;R¹ is chosen from (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andH₂N—CO—(C₁-C₄)-alkyl-;R¹⁰ is chosen from hydrogen, (C₁-C₆)-alkyl-O—CO— and(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—;R²⁰ is chosen from phenyl and heteroaryl which are optionallysubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—,hydroxy and cyano;R³⁰ is chosen from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,tetrahydropyranyl, phenyl and heteroaryl, wherein cycloalkyl andcycloalkenyl are optionally substituted by one or more identical ordifferent substituents chosen from fluorine, (C₁-C₄)-alkyl and hydroxy,and phenyl and heteroaryl are optionally substituted by one or moreidentical or different substituents chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano;R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, HO—CO—, (C₁-C₄)-alkyl-O—CO—and H₂N—CO—, wherein all substituents R⁴⁰ are independent of each otherand can be identical or different;heteroaryl is chosen from thiophenyl and pyridinyl;m is chosen from 0, 1 and 2, wherein all numbers m are independent ofeach other and can be identical or different;n is chosen from 0, 1 and 2;p and q are 2;u is chosen from 0, 1 and 2, wherein all numbers u are independent ofeach other and can be identical or different;v is chosen from 0, 1 and 2;wherein all alkyl groups, independently of each other, are optionallysubstituted by one or more fluorine atoms;wherein the cycloalkyl group is optionally substituted by one or moreidentical or different substituents chosen from flourine and(C₁-C₄)-alkyl, unless specified otherwise;wherein all phenyl groups present in R and R⁴⁰, independently of eachother, are optionally substituted by one or more identical of differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)₂— and cyano.

Another such example are compounds of the formula I, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and the physiologically acceptable salts thereof, and thephysiologically acceptable solvates of any of them, wherein

A is chosen from O and C(R^(a))₂;R^(a) is hydrogen;R is chosen from hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andR¹—NH—CO—C_(u)H_(2u)—, wherein all groups R are independent of eachother and can be identical or different;R¹ is chosen from (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- andH₂N—CO—(C₁-C₄)-alkyl-;R¹⁰ is hydrogen;R²⁰ is phenyl which is optionally substituted by one or more identicalor different substituents chosen from halogen and (C₁-C₄)-alkyl;R³⁰ is chosen from (C₅-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl,tetrahydropyranyl and phenyl, wherein phenyl is optionally substitutedby one or more identical or different substituents chosen from halogen,(C₁-C₆)-alkyl, hydroxy, (C₁-C₆)-alkyl-O— and(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—;R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl, hydroxy, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—CO— and H₂N—CO—,wherein all substituents R⁴⁰ are independent of each other and can beidentical or different;n is chosen from 0, 1 and 2;p and q are 2;u is chosen from 0, 1 and 2, wherein all numbers u are independent ofeach other and can be identical or different;wherein all alkyl groups, independently of each other, are optionallysubstituted by one or more fluorine atoms.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I, including their salts andsolvates, which are outlined below and by which the compounds areobtainable. For example, the preparation of the compounds of the formulaI can be carried out by first reacting an indole of the formula II onthe ring nitrogen atom with an alkylating or arylating compound of the

formula III to give a compound of the formula IV which is then convertedinto a 1,3-dihydro-indol-2-one (oxindole) of the formula V. The groupsR³⁰ and R⁴⁰ and the number n in the compounds of the formulae II, III,IV and V are defined as in the compounds of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which is later converted into the finalgroup. The group X¹ in the compounds of the formula III is asubstitutable group allowing a nucleophilic substitution reaction or areaction of another mechanistic type, including radical reactions andtransition metal-catalyzed reactions, which results in the replacementof such a substitutable group by the ring nitrogen atom in the compoundof the formula II, for example halogen or an arylsulfonyloxy oralkylsulfonyloxy group or a boron-containing group.

In case R³⁰ is optionally substituted phenyl or heteroaryl which issubstituted with a suitable electron-accepting group or comprises anelectron-deficient heterocyclic ring, or R³⁰ is optionally substitutedcycloalkyl or cycloalkenyl or is tetrahydropyranyl, X¹ can be halogen,in particular chlorine, bromine or iodine, or an arylsulfonyloxy oralkylsulfonyloxy group such as benzenesulfonyloxy, toluenesulfonyloxy,nitrobenzenesulfonyloxy, methanesulfonyloxy ortrifluoromethanesulfonyloxy, and the reaction can be performed under theconditions of a nucleophilic substitution reaction, usually in asolvent, for example an inert aprotic solvent such as an ether liketetrahydrofuran (THF), dioxane (1,4-dioxane) or ethylene glycol dimethylether (DME), an amide like dimethylformamide (DMF) orN-methyl-pyrrolidin-2-one (NMP), or dimethyl sulfoxide (DMSO), or amixture thereof, and in the presence of a base such as an alcoholatelike sodium ethoxide or potassium tert-butoxide, a hydride like sodiumhydride, an amide like sodium amide or lithium diisopropylamide, acarbonate like potassium carbonate or cesium carbonate, or an amine likeethyldiisopropylamine.

In case R³⁰ is optionally substituted phenyl or heteroaryl, X¹ can bechlorine, bromine or iodine, i.e. the compound of the formula III be anoptionally substituted chlorobenzene, bromobenzene, iodobenzene,chloroheteroarene, bromoheteroarene or iodoheteroarene, and the reactionof the compounds of the formula II and III can be performed under theconditions of the Ullmann arylation reaction in the presence of acatalytic copper compound, for example copper(I) bromide, copper(I)iodide or copper(II) acetylacetonate, at elevated temperatures, forexample at temperatures from about 100° C. to about 150° C., usually inan inert aprotic solvent such as DMSO, DMF, NMP, acetonitrile, dioxaneor toluene in the presence of a base such as a carbonate like potassiumcarbonate or cesium carbonate or a phosphate like tribasic potassiumphosphate and favorably an amine like N,N′-dimethylethylenediamine,1,2-diaminocyclohexane, proline or 8-hydroxyquinoline. The arylationreaction, like other reactions performed in the synthesis of thecompounds of the formula I, can also be carried out in a microwavereactor.

In another method for the preparation of compounds of the formula IV acompound of the formula II can be reacted with a compound of the formulaIII in which R³⁰ is optionally substituted phenyl or heteroaryl and X¹is halogen, in particular chlorine, bromine or iodine, or analkylsulfonyloxy group such as trifluoromethanesulfonyloxy, in thepresence of a palladium catalyst, which can be formed fromtris(dibenzylideneacetone)dipalladium(0) and a phosphine ligand, forexample, and a base such as sodium tert-butoxide or tribasic potassiumphosphate in an inert solvent such as a hydrocarbon like toluene or anether like dioxane at temperatures from about 60° C. to about 120° C.,as described in D. W. Old et al., Org. Lett. 2 (2000), 1403, forexample.

In a further method for the preparation of compounds of the formula IV,a compound of the formula II can be reacted with a boronic acid, i.e. acompound of the formula III wherein X¹ is a boronic acid group B(OH)₂,in a transition metal-catalyzed reaction for example according to theChan-Evans-Lam modification of the Suzuki-Miyaura coupling reaction inthe presence of a copper compound such as copper(II) acetate in asolvent such as a chlorinated hydrocarbon like dichloromethane orchloroform at temperatures from about 20° C. to about 40° C., forexample at room temperature, and in the presence of a tertiary aminesuch as triethylamine, ethyldiisopropylamine or pyridine, as describedin D. M. T. Chan et al., Tetrahedron Lett. 39 (1998), 2933, for example.Instead of with a boronic acid, a compound of the formula IV can also beobtained from a compound of the formula II with an organotrifluoroboratesalt, i.e. a compound of the formula III wherein X¹ is a negativelycharged trifluoroborate group BF₃ ⁻ having a cation such as an alkalinemetal cation like a cesium, potassium, sodium or lithium cation or aquaternary ammonium or phosphonium cation, in particular a potassiumcation, as counterion (cf. R. A. Batey et al., Tetrahedron Lett. 42(2001), 9099), in the presence of a catalytic transition metal compoundsuch as a copper compound like copper(II) acetate in a solvent such as achlorinated hydrocarbon like dichloromethane or chloroform attemperatures from about 20° C. to about 50° C. in the presence of oxygenand molecular sieves, as described in T. D. Quach et al., Org. Lett.(2003), 4397, for example.

The subsequent conversion of the compound of the formula IV into theoxindole of the formula V can be carried out by first treating thecompound of the formula IV with N-chlorosuccinimide in a solvent such asa chlorinated hydrocarbon like dichloromethane at temperatures fromabout 10° C. to about 30° C., for example at room temperature, and thentreating the crude intermediate product with 85% phosphoric acid inacetic acid at elevated temperatures from about 110° C. to about 140°C., as described in R. Sarges et al., J. Med. Chem. 32 (1989), 437. Theconversion of a compound of the formula IV to an oxindole of the formulaV can also be carried out by first treating the compound of the formulaIV with bromine or a bromine source such as N-bromosuccinimide orpyridinium bromide perbromide (pyridinium tribromide) in a solvent suchas a chlorinated hydrocarbon like dichloromethane or an alcohol liketert-butanol or amyl alcohol or a mixture of an alcohol and water or anaqueous buffer solution like a phosphate buffer having a pH of about 5,for example, at temperatures from about 0° C. to about 50° C. Reductionof intermediate bromine-containing products or hydrolysis to theoxindole of the formula V can then be carried out by treatment with ametal such as zinc or iron in acetic acid or a mixture of acetic acidand a solvent such as an alcohol like methanol, ethanol or tert-butanolor an ether like diethyl ether or THF, or by hydrogenation in thepresence of a hydrogenation catalyst such as palladium hydroxide orpalladium on carbon or Raney nickel, for example, in a solvent such asan alcohol like methanol or ethanol or an ester like ethyl acetate attemperatures from about 0° C. to about 60° C. and a hydrogen pressurefrom about 1 bar to about 100 bar, as described in J. Parrick et al.,Tetrahedron Lett. 25 (1984), 3099; A. Marfat et al., Tetrahedron Lett.28 (1987), 4027; or R. P. Robinson et al., J. Org. Chem. 56 (1991),4805, for example.

Compounds of the formula V can also be obtained by reacting an oxindoleof the formula VI, wherein the group R⁴⁰ and the number n are defined asin the compound of the formula I and additionally functional groups canbe present in protected form or in the form of a precursor group whichis later converted into the final group, with a compound of the formulaIII as defined above, wherein X¹ is halogen or an arylsulfonyloxy oralkylsulfonyloxy group or a boron-containing group such as a boronicacid group or the group BF₃ ⁻ having a cation like a potassium cation ascounterion, in a nucleophilic substitution reaction or an Ullmannreaction or another transition metal-catalyzed reaction as outlinedafore. The explanations given above with respect to the reaction of thecompounds of the formulae II and III, for example regardingpalladium-catalyzed and copper-catalyzed reactions, applycorrespondingly with respect to the reaction of the compounds of theformulae VI and III.

In the course of the synthesis of the compounds of the formula I, theoxindoles of the formula V can then be subjected to a Vilsmeierformylation with concomitant chlorination to give the1-R³⁰-2-chloro-indole-3-carboxaldehydes of the formula VII,

wherein the groups R³⁰ and R⁴⁰ and the number n are defined as in thecompound of the formula I and additionally functional groups can bepresent in protected form or in the form of a precursor group which islater converted into the final group. The Vilsmeier formylation reagentcan conveniently be prepared in situ from dimethylformamide and asuitable inorganic or organic chloride such as phosgene, oxalyl chlorideor phosphorus oxychloride in an inert aprotic solvent such as ahydrocarbon or chlorinated hydrocarbon like benzene, dichloromethane orchloroform, an ether like DME or an excess of DMF, or a mixture thereof,at temperatures from about 0° C. to about 10° C. Preferably, phosphorusoxychloride is employed. The reaction of the Vilsmeier reagent with thecompound of the formula V is usually carried out at temperatures fromabout 0° C. to about 30° C., preferably in the presence of a base suchas pyridine. Hydrolytic workup of the reaction mixture, which like theworkup of all reactions in the preparation of the compounds of theformula I can generally be performed under standard conditions, thenyields the aldehyde of the formula VII.

Compounds of the formula VII can also be obtained by first subjecting anoxindole of the formula VI to a Vilsmeier formylation with concomitantchlorination in the 2-position analogously as outlined afore to give the2-chloro-indole-3-carboxaldehydes of the formula VIII, wherein the groupR⁴⁰ and the number n are defined as in the compound of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which is later converted into the finalgroup, and then introducing the group R³⁰ in the 1-position of theindole ring in the compound of the formula VIII by reaction with acompound of the formula III as defined above, wherein X¹ is halogen oran arylsulfonyloxy or alkylsulfonyloxy group or a boron-containing groupsuch as a boronic acid group or the group BF₃ ⁻ having a cation like apotassium cation as counterion, in a nucleophilic substitution reactionor an Ullmann reaction or another transition metal-catalyzed reaction asoutlined afore. The explanations given above with respect to thereaction of the compounds of the formulae II and III, for exampleregarding palladium-catalyzed and copper-catalyzed reactions, applycorrespondingly with respect to the reaction of the compounds of theformulae VIII and III.

The indole-3-carboxaldehydes of the formula VII can then be oxidizedunder standard conditions for the oxidation of aldehydes to carboxylicacids to give the indole-3-carboxylic acids of the formula IX, whereinthe groups R³⁰ and R⁴⁰ and the number n are defined as in the compoundof the formula I and additionally functional groups can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. For example, the oxidation can beperformed with a permanganate such as potassium permanganate in amixture of water and an inert organic solvent, such as a ketone likeacetone or an ether like THF, at temperatures from about 10° C. to about30° C., for example at room temperature, at about neutral pH values.Conveniently, the oxidation can also be accomplished with a chloritesuch as sodium chlorite in the presence of 2-methylbut-2-ene in mixtureof water and an inert organic solvent, such as an alcohol liketert-butanol or an ether like THF, at temperatures from about 10° C. toabout 30° C., for example at room temperature, at weakly acidic pHvalues, for example in the presence of a dihydrogenphosphate.

The carboxylic acid of the formula IX can then be coupled under standardconditions for the formation of an amide bond with a diazacycloalkane ofthe formula X to give a compound of the formula XI. The groups R, R³⁰and R⁴⁰ and the numbers n, p and q in the compounds of the formulae Xand XI are defined as in the compounds of the formula I and additionallyfunctional groups can be present in protected form or in the form of aprecursor group which is later converted into the final group. Thecompounds of the formula VII are defined as above. The group R⁵⁰ in thecompounds of the formulae X and XI can have the meanings of the groupR¹⁰ in the compounds of the formula I with the exception of hydrogen,i.e. it can be (C₁-C₆)-alkyl-O—CO— or(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—, which groups protect the nitrogenatom carrying R⁵⁰ against a reaction with the compound of the formulaIX, or R⁵⁰ can be another protective group which prevents a reaction atthe said nitrogen atom and can later be removed to give a final compoundof the formula I in which R¹⁰ is hydrogen. Examples of groups whichprevent a reaction at the said nitrogen atom, are the benzyloxycarbonylgroup which can later be cleaved by hydrogenation in the presence of acatalyst such as a palladium catalyst, the tert-butyloxycarbonyl groupwhich can later be cleaved by treatment with an acid such astrifluoroacetic acid or hydrogen chloride, or thefluoren-9-yloxycarbonyl group which can later be cleaved by treatmentwith piperidine. For the formation of the amide bond, the carboxylicacid of the formula IX is usually converted into a reactive derivative,which can be isolated or prepared in situ, or activated in situ by acustomary amide coupling reagent. For example, the compound of theformula IX can be converted into an acid chloride by treatment withthionyl chloride, oxalyl chloride or(1-chloro-2-methyl-propenyl)-dimethylamine, into a reactive ester, orinto a mixed anhydride by treatment with an alkyl chloroformate likeethyl chloroformate or isobutyl chloroformate, or it can be activatedwith a reagent such as propanephosphonic anhydride, anN,N′-carbonyldiazole like N,N′-carbonyldiimidazole (CD), a carbodiimidelike N,N′-diisopropylcarbodiimide (DIC), N,N′-dicyclohexylcarbodiimide(DCC) or N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDC), a carbodiimide together with an additive like1-hydroxybenzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), auronium-based coupling reagent likeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) orO-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), or a phosphonium-based coupling reagent like(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP) or bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP). The activation of the compound of theformula IX and the reaction of the activated compound of the formula IXor a reactive derivative of the compound of the formula IX with thecompound of the formula X is generally carried out in an inert solvent,such as an ether like THF, dioxane or DME, a hydrocarbon such astoluene, a chlorinated hydrocarbon like dichloromethane or chloroform,or an amide such as DMF or NMP, for example, or a mixture of solvents,at temperatures from about 0° C. to about 60° C. in the presence of asuitable base such a tertiary amine like triethylamine,ethyldiisopropylamine, N-methylmorpholine or pyridine, or a basic alkalimetal compound such as an alkali metal carbonate like sodium carbonate,potassium carbonate or cesium carbonate, for example.

The obtained compound of the formula XI can then be reacted with acompound of the formula XII to give a compound of the formula XIII. Thegroups A, R, R²⁰, R³⁰ and R⁴⁰ and the numbers n, p and q in thecompounds of the formulae XII and XIII are defined as in the compoundsof the formula I and additionally functional groups can be present inprotected form or in the form of a precursor group which is laterconverted into the final group. The group R⁵⁰ in the compound of theformula XIII is defined as in the compounds of the formulae X and XI. Incase the group A in the compound of the formula XII is O, S orN((C₁-C₄)-alkyl), the group X² is hydrogen, and the reaction of thecompounds of the formulae XI and XII is a nucleophilic substitutionreaction. In such case, as applies in general to all starting compoundsand intermediates in the synthesis of the compounds of the formula Iincluding the compounds of the formulae IX, X and XII, for example, thesaid compounds of the formula XII in which X² is hydrogen can also beemployed in the form of a salt. Likewise, all products obtained in thecourse of the synthesis of the compounds of the formula I, including thefinal compounds of the formula I, can be obtained in the form of a salt.Examples of suitable salts of the compounds of the formula XII, whichcan also be prepared in situ, are alkaline metal salts such as sodiumsalts and potassium salts and salts comprising an inert ammonium cationsuch as quaternary ammonium salts. The reaction of a compound of theformula XII, wherein A is O, S or N((C₁-C₄)-alkyl) and X² is hydrogen,with a compound of the formula XI is usually carried out in a solvent,for example an inert aprotic solvent such as an amide like DMF or NMP,or DMSO, or a mixture of solvents, in the presence of a base such as analcoholate like sodium ethoxide or potassium tert-butoxide, a hydridelike sodium hydride or potassium hydride, or an amide like sodium amideor lithium diisopropylamide, at elevated temperatures from about 80° C.to about 180° C. Advantageously, the reaction can be carried out in amicrowave reactor. In case the group A in the compound of the formulaXII is C(R^(a))₂, the reaction of the compounds of the formulae XI andXII to give the compound of the formula XIII is favorably carried outvia an organometallic compound. For example, in such case the compoundof the formula XII can be an organometallic compound such as anorganozinc compound like an organozinc chloride or organozinc bromide,the group X² in the compound of the formula XII then being the groupZn—Cl or Zn—Br, or an organoboron compound like a9-organo-9-borabicyclo[3.3.1]nonane, the group X² in the compound of theformula XII then being a 9-borabicyclo[3.3.1]nonan-9-yl group. Withrespect to the compound of the formula XII which is actually employed inthe reaction in case A is C(R^(a))₂, the group X² in the compound of theformula XII can also be regarded to be halogen such as chlorine orbromine, and this compound of the formula XII is then converted in situby treatment with zinc into the respective organozinc compound or intoan organoboron compound. The reaction of an organozinc compound of theformula XII with the compound of the formula XI is generally carried outin an inert aprotic solvent such as a hydrocarbon like hexane, benzeneor toluene, an ether like THF or dioxane, or an amide like DMF or NMP,or a mixture of solvents, at temperatures from about 0° C. to about 120°C., favorably in the presence of a transition metal catalyst, such as inthe presence of a palladium compound like palladium(II) acetate,tris(dibenzylideneacetone)dipalladium(0) orbis(dibenzylideneacetone)palladium(0) together with a phosphine ligandlike 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, for example,and additionally an alkoxyborane derivative likeB-methoxy-9-borabicyclo[3.3.1]nonane, or in the presence of a nickelcompound like nickel acetylacetonate. In the reaction of an organoboroncompound of the formula XII with the compound of the formula XIgenerally a base such as tribasic potassium phosphate, for example, isadded.

In another method for the preparation of a compound of the formula XIIIfrom a compound of the formula XI and a compound of the formula XIIwherein A is C(R^(a))₂, the compound of the formula XI is firstconverted into the respective organolithium compound which comprises alithium atom instead of the chlorine atom in the 2-position, for exampleby reaction with an alkyllithium compound such as n-butyllithium, andthis intermediary organolithium compound is then reacted in asubstitution reaction with a compound of the formula XII wherein thegroup X² is a nucleophilically substitutable leaving group such ashalogen, in particular chlorine, bromine or iodine, or anarylsulfonyloxy or alkylsulfonyloxy group such as benzenesulfonyloxy,toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy.The lithiation of the compound of the formula XI and subsequentalkylation are generally carried out in an inert aprotic solvent such asa hydrocarbon like hexane or benzene or an ether like THF or dioxane ora mixture of solvents at temperatures from about −80° C. to about 30° C.

In case the group R⁵⁰ in the compound of the formula XIII has any of themeanings of the group R¹⁰ in the compounds of the formula I and allother groups have the desired meanings comprised by the definition ofthe compounds of the formula I, the compound of the formula XIII thusobtained is already a final compound of the formula I. In case R⁵⁰ is aprotective group and a compound of the formula I is to be prepared inwhich R¹⁰ is hydrogen, and/or any other groups are present in protectedform or in the form of a precursor group, the compound of the formulaXIII thus obtained can finally be converted into the desired compound ofthe formula I by removal of protection groups and/or conversion of anyother groups. As indicated above, in order to avoid an undesired courseof a reaction or side reactions, in any one or more steps in thesynthesis of the compounds of the formula I functional groups can bepresent in protected form or in the form of a precursor group. Besidesin the final step of the synthesis of a compound of the formula I,protective groups can be removed, and precursor groups be converted,also at other stages of the synthesis. Respective synthetic strategiesand details about suitable protective groups and their introduction andremoval are well known to a person skilled in the art and are found inP. G. M. Wuts and T. W. Greene, Greene's Protective Groups in OrganicSynthesis, 4. ed. (2007), John Wiley & Sons, for example. Examples ofprotective groups which may be mentioned, are benzyl protective groupssuch as in benzyl ethers of hydroxy groups and benzyl esters ofcarboxylic acid groups from which the benzyl group can be removed bycatalytic hydrogenation in the presence of a palladium catalyst,tert-butyl protective groups such as in tert-butyl esters of carboxylicacid groups from which the tert-butyl group can be removed by treatmentwith trifluoroacetic acid, acyl protective groups which protect hydroxygroups and amino groups in the form of esters and amides and which canbe cleaved by acidic or basic hydrolysis, and alkyloxycarbonylprotective groups such as in tert-butoxycarbonyl derivatives of aminogroups, including the cyclic amino group being part of thediazacycloalkane moiety depicted in formula I in case R¹⁰ is hydrogen,which can be cleaved by treatment with trifluoroacetic acid. Examples ofprecursor groups which may be mentioned are nitro groups which can beconverted to amino groups by catalytic hydrogenation or by reductionwith sodium dithionite, for example, and cyano groups which can beconverted to carboxamide groups and carboxylic acid groups byhydrolysis.

In addition, in order to obtain further compounds of the formula I,various other transformations of functional group can be carried out incompounds of the formula I or compounds of the formula XIII or othercompounds occurring in the synthesis of the compounds of the formula I.For example, a hydroxy group in a compound of the formula I or XIII canbe etherified or esterified or reacted with an isocyanate to give acarbamate under standard conditions. Etherifications of hydroxy groupscan favorably be performed by alkylation with the respective halogencompound, in particular a bromide or iodide, in the presence of a basesuch an alkali metal carbonate like potassium carbonate or cesiumcarbonate in an inert solvent such as an amide like DMF or NMP or aketone like acetone or butan-2-one, or with the respective alcohol underthe conditions of the Mitsunobu reaction in the presence of anazodicarboxylate like diethyl azodicarboxylate or diisopropylazodicarboxylate and a phosphine like triphenylphosphine ortributylphosphine in an inert aprotic solvent such as an ether like THFor dioxane (cf. O. Mitsunobu, Synthesis (1981), 1). An amino group in acompound of the formula I or XIII can be modified under standardconditions for alkylation, for example by reaction with a halogencompound or by reductive amination of a carbonyl compound, or foracylation or sulfonylation, for example by reaction with an activatedcarboxylic acid or a carboxylic acid derivate like an acid chloride oranhydride or a sulfonic acid chloride. A carboxylic acid group in acompound of the formula I or XIII can be activated or converted into areactive derivative as outlined above with respect to the compounds ofthe formula IX and reacted with an alcohol or amine to give an ester oramide. An alkyl-S— group in a compound of the formula I or XIII can beoxidized with a peroxide like hydrogen peroxide or a peracid to give analkyl-S(O)— or alkyl-S(O)₂— group, and a protected mercapto group in acompound of the formula XIII can be deprotected and oxidized to give asulfonic acid which can then be activated and reacted with an amineunder standard conditions to give a sulfonamide.

The order in which groups are introduced in the course of the synthesisof a compound of the formula I, can also be different from the onesoutlined above. For example, instead of first introducing thediazacycloalkane moiety and then the moiety -A-R²⁰ by reacting acompound of the formula IX with a compound of the formula X and reactingthe obtained compound of the formula XI with a compound of the formulaXII, it is also possible to introduce first the moiety -A-R²⁰ and thenthe diazacycloalkane moiety by reacting a compound of the formula IX ora protected form thereof such as an ester with a compound of the formulaXII and, optionally after deprotection, reacting the obtained compoundof the formula XIV with a compound of the formula X to give a compoundof the formula XIII which can finally be converted into the desiredcompound of the formula I, for example by removing the protective groupR⁵⁰ in the case of the preparation of a compound of the formula I inwhich R¹⁰ in the compound of the formula I is hydrogen.

The groups A, R²⁰, R³⁰ and R⁴⁰ and the number n in the compounds of theformula XIV are defined as in the compounds of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which are later converted into the finalgroup. Besides that, as mentioned, in the employed compounds of theformula IX the carboxylic acid depicted in the formula can be present inprotected form, for example in the form of an ester like a tert-butylester or a benzyl ester, when reacting the compounds of the formulae IXand XII, and the carboxylic acid group in the compound of the formulaXIV can thus also be present in protected form and is deprotected beforereacting the compounds of the formulae X and XIV. The compounds of theformulae IX, X, XII and XIII are defined as above. All explanationsgiven above with respect to the reaction of the compounds of the formulaXI with the compounds of the formula XII, and the reaction of thecompounds of the formula IX with the compounds of the formula X, applycorrespondingly to the reaction of the compounds of the formula IX withthe compounds of the formula XII, and the reaction of the compounds ofthe formula X with the compounds of the formula XIV, respectively. Thus,for example, for the formation of the amide bond in the reaction of thecompounds of the formulae X and XIV the carboxylic acid group isgenerally converted into a reactive derivative or activated by means ofa customary amide coupling reagent and reacted with the compound of theformula X in the presence of a base as outlined above.

In a further strategy for the synthesis of the compounds of the formulaI, the moiety -A-R²⁰ can be also introduced into an aldehyde of theformula VII by reacting it with a compound of the formula XII to give acompound of the formula XV, the aldehyde group in the compound of theformula XV then be oxidized to give a compound of the formula XIV, andthe latter compound then reacted with a compound of the formula X tofinally give a compound of the formula I as already outlined above.

The groups A, R²⁰, R³⁰ and R⁴⁰ and the number n in the compounds of theformula XV are defined as in the compounds of the formula I andadditionally functional groups can be present in protected form or inthe form of a precursor group which are later converted into the finalgroup. The compounds of the formulae VII, X, XII and XIV are defined asabove. All explanations given above with respect to the reaction of thecompounds of the formula XI or the formula IX with the compounds of theformula XII, and with respect to the oxidation of the compounds of theformula VII to the compounds of the formula IX, apply correspondingly tothe reaction of the compounds of the formula VII with the compounds ofthe formula XII and the oxidation of the compounds of the formula XV tothe compounds of the formula XIV, respectively. Thus, for example, theoxidation of the aldehyde group in the compounds of the formula XIV canconveniently be performed with sodium chlorite in the presence of2-methylbut-2-ene or with potassium permanganate in a mixture of waterand an organic solvent as outlined above.

All reactions carried out in the preparation of the compounds of theformula I are known per se and can be carried out in manner familiar toa person skilled in the art by or analogously to procedures which aredescribed in the standard literature, for example in Houben-Weyl,Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley &Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2. ed. (1999), John Wiley & Sons, and thereferences quoted therein.

The starting compounds and building blocks for the synthesis of thecompounds of the formula I are commercially available or can be preparedaccording to procedures described in the literature or analogously tosuch procedures. If desired, indoles of the formula II can be preparedaccording to the procedures of the well-known Fischer indole synthesis,in which an optionally substituted phenylhydrazone is cyclized, or theBischler indole synthesis, in which an optionally substituted2-anilinoketone is cyclized, for example, and oxindoles of the formulaVI can be prepared by cyclizing optionally substituted2-chloro-acetanilides. In order to prepare specifically substitutedindoles of the formula II, it is furthermore possible to reduce a1H-indole to a 2,3-dihydro-1H-indole, for example by hydrogenation,subject the latter compound to a electrophilic aromatic substitutionreaction which allows the introduction of substituents into the benzenering which cannot be introduced by subjecting the indole to such areaction, and subsequently dehydrogenating the 2,3-dihydro-1H-indole togive an indole again, for example by means of chloranil, manganesedioxide or palladium together with a hydrogen acceptor. As examples ofarticles in which syntheses and reactions of indoles are described, G.R. Humphrey et al., Chem. Rev. 106 (2006), 2875; and R. J. Sundberg,Indoles (Best Synthetic Methods), Academic Press, London, San Diego(1996), may be mentioned. As another example of procedures for thepreparation of starting compounds and building blocks, the processes forthe preparation of substituted phenols described in US 2006/0160786 andin Organikum, 12. ed., VEB Deutscher Verlag der Wissenschaften, Berlin(1973), 588, may be mentioned, according to which compounds of theformula XII in which X² is hydrogen, A is O and R²⁰ is substitutedphenyl, can be prepared, such as 3-fluoro-2-methyl-phenol,2-fluoro-6-methyl-phenol or 3,5-difluoro-2-methyl-phenol, for example.

Another subject of the present invention are the novel startingcompounds and intermediates occurring in the synthesis of the compoundsof the formula I, including the compounds of the formulae II, III, IV,V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV, wherein A, R, R²⁰,R³⁰, R⁴⁰, R⁵⁰, X¹, X², n, p and q are defined as above, in any of theirstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,and their salts, and solvates of any of them, and their use asintermediates. The general explanations, preferred definitions of groupsand numbers and embodiments of the invention given above with respect tothe compounds of the formula I apply correspondingly to the saidintermediates and starting compounds. A subject of the invention are inparticular the novel specific starting compounds and intermediatesdisclosed herein. Independently thereof whether they are disclosed as afree compound and/or as a specific salt, they are a subject of theinvention both in the form of the free compounds and in the form oftheir salts, and if a specific salt is disclosed, additionally in theform of this specific salt, and in the form of solvates of any of them.

The compounds of the formula I inhibit the enzyme renin as can bedemonstrated in the pharmacological tests described below and in otherpharmacological tests which are known to a person skilled in the art,for example in in vitro tests in which the inhibition of human renin isdetermined, or in animal models in which the antihypertensive activityand other effects are determined in vivo. The compounds of the formula Iare suitable for the treatment of hypertension including pulmonaryhypertension, for example, and other disorders of the cardiovascularsystem and heart diseases, such as heart failure, cardiac infarction,angina pectoris, cardiac insufficiency, cardiac failure, cardiachypertrophy, cardiac fibrosis, vascular hypertrophy, left ventriculardysfunction, in particular left ventricular dysfunction after myocardialinfarction, endothelial dysfunction, ischemic and obstructive peripheralcirculation disorders and restenosis including restenosispost-angioplasty, for example, for the treatment of renal diseases suchas renal fibrosis, renal ischemia, renal failure and kidneyinsufficiency, for example, and for the treatment of other diseases, forexample diabetes complications, such as nephropathy and retinopathy,cerebral afflictions, such as cerebral hemorrhage, glaucoma, andend-organ damage. The treatment of diseases is to be understood asmeaning both the therapy of existing pathological changes ormalfunctions of the organism or of existing symptoms with the aim ofrelief, alleviation or cure, and the prophylaxis or prevention ofpathological changes or malfunctions of the organism or of symptoms inhumans or animals which are susceptible thereto and are in need of sucha prophylaxis or prevention, with the aim of prevention or suppressionof their occurrence or of an attenuation in the case of theiroccurrence. For example, in patients who on account of their diseasehistory are susceptible to ventricular dysfunction after myocardialinfarction, by means of the prophylactic or preventive medicinaltreatment the occurrence of ventricular dysfunction can be prevented orits extent and sequelae decreased. The treatment of diseases can occurboth in acute cases and in chronic cases.

The compounds of the formula I and their physiologically acceptablesalts and physiologically acceptable solvates thereof can therefore beused in animals, in particular in mammals and specifically in humans, asa pharmaceutical or medicament on their own, in mixtures with oneanother or in the form of pharmaceutical compositions. A subject of thepresent invention also are the compounds of the formula I and theirphysiologically acceptable salts and physiologically acceptable solvatesthereof for use as a pharmaceutical, as well as pharmaceuticalcompositions and medicaments which comprise an efficacious dose of atleast one compound of the formula I and/or a physiologically acceptablesalt thereof and/or a physiologically acceptable solvate of any of themas an active ingredient and a pharmaceutically acceptable carrier, i.e.one or more pharmaceutically innocuous vehicles and/or excipients. Asubject of the present invention furthermore are the compounds of theformula I and their physiologically acceptable salts and physiologicallyacceptable solvates thereof for use in the treatment of the diseasesmentioned above or below, for example of hypertension, or for theinhibition of renin, as well as the use of the compounds of the formulaI and their physiologically acceptable salts and physiologicallyacceptable solvates thereof for the manufacture of a medicament for thetreatment of the diseases mentioned above or below, for example ofhypertension, or for the manufacture of a medicament for the inhibitionof renin, wherein the treatment of diseases comprises their therapy andprophylaxis. A subject of the invention also are methods for thetreatment of the diseases mentioned above or below, which compriseadministering an efficacious amount of at least one compound of theformula I or a physiologically acceptable salt thereof or aphysiologically acceptable solvate of any of them to a human or ananimal which is in need thereof. The compounds of the formula I andpharmaceutical composition and medicaments comprising them can beadministered enterally, for example by oral, buccal, sublingual orrectal administration, parenterally, for example by intravenous,intramuscular or subcutaneous injection or infusion, or by another typeof administration such as topical, percutaneous, transdermal,intratracheal, intranasal or intraocular administration.

The pharmaceutical compositions and medicaments according to theinvention normally contain about 0.5 to about 90 percent by weight ofcompounds of the formula I and/or their physiologically acceptable saltsand/or physiologically acceptable solvates thereof. The amount of activeingredient of the formula I and/or its physiologically acceptable saltand/or a physiologically acceptable solvate of any of them in thepharmaceutical compositions and medicaments is in general about 0.2 mgto about 1000 mg, preferably about 0.2 mg to about 500 mg, particularlypreferably about 1 mg to about 300 mg, per unit dose. The production ofthe pharmaceutical compositions and medicaments can be carried out in amanner known per se. For this, the compounds of the formula I and/ortheir physiologically acceptable salts and/or physiologically acceptablesolvates thereof are mixed together with one or more solid or liquidvehicles and/or excipients, if desired also in combination with one ormore other active ingredients such as, for example, an angiotensinconverting enzyme inhibitor, an angiotensin receptor antagonist, adiuretic, an endothelin receptor antagonist, an endothelin convertingenzyme inhibitor, a neutral endopeptidase inhibitor, a calcium channelblocker, a nitrate like isosorbiddinitrate, a β-receptor blocker, an α1adrenoreceptor antagonist, a cannabinoid receptor antagonist, apotassium channel modulator, a thromboxane synthetase inhibitor, ananti-serotoninergic agent, or another agent useful for treatinghypertension, heart failure, vascular diseases related to diabetes orrenal diseases such as acute or chronic renal failure, for example, andare brought into a suitable form for dosage and administration which canthen be used in human medicine or veterinary medicine. A subject of thepresent invention also is in particular a pharmaceutical compositionwhich comprises an efficacious dose of at least one compound of theformula I and/or a physiologically acceptable salt thereof and/or aphysiologically acceptable solvate of any of them and one or more otheractive ingredients and a pharmaceutically acceptable carrier, whereinthe other active ingredients are useful for the treatment ofhypertension, cardiac infarction, heart failure, vascular diseasesrelated to diabetes, end-organ damage such as cardiac insufficiency orkidney insufficiency, renal diseases such as acute or chronic renalfailure, restenosis or glaucoma, and wherein as examples of such otheractive ingredients angiotensin converting enzyme inhibitors, angiotensinreceptor antagonists, diuretics, endothelin receptor antagonists,endothelin converting enzyme inhibitors, neutral endopeptidaseinhibitors, calcium channel blockers, nitrates like isosorbiddinitrate,β-receptor blockers, α1 adrenoreceptor antagonists, cannabinoid receptorantagonists, potassium channel modulators, thromboxane synthetaseinhibitors and anti-serotoninergic agents may be mentioned.

As vehicles and excipients, suitable organic and inorganic substancescan be used which do not react in an undesired manner with the compoundsof the formula I. Examples which may be mentioned are water, vegetableoils, waxes, alcohols such as ethanol, isopropanol, 1,2-propanediol,benzyl alcohols or glycerol, polyols, polyethylene glycols,polypropylene glycols, glycerol triacetate, gelatin, carbohydrates suchas lactose or starch, stearic acid and its salts such as magnesiumstearate, talc, lanolin, petroleum jelly, or mixtures thereof, forexample mixtures of water with one or more organic solvents such asmixtures of water with alcohols. For oral and rectal use, in particularpharmaceutical forms such as, for example, tablets, film-coated tablets,sugar-coated tablets, granules, hard and soft gelatin capsules,suppositories, solutions, preferably oily, alcoholic or aqueoussolutions, syrups, juices or drops, furthermore suspensions oremulsions, can be used. For parenteral use, for example by injection orinfusion, in particular pharmaceutical forms such as solutions,preferably aqueous solutions, can be used. For topical use, inparticular pharmaceutical forms such as ointments, creams, pastes,lotions, gels, sprays, foams, aerosols, solutions or powders can beused. Further suitable pharmaceutical forms are, for example, implantsand patches. and forms adapted to inhalation. The compounds of theformula I and their physiologically acceptable salts and physiologicallyacceptable solvates of any of them can also be lyophilized and theobtained lyophilizates obtained used, for example, for the production ofinjectable compositions. In particular for topical application,liposomal compositions are also suitable. As examples of types ofexcipients or additives which can be contained in the pharmaceuticalcompositions and medicaments, lubricants, preservatives, thickeners,stabilizers, disintegrants, wetting agents, agents for achieving a depoteffect, emulsifiers, salts, for example for influencing the osmoticpressure, buffer substances, colorants and flavoring substances may bementioned. The pharmaceutical compositions and medicaments can alsocontain one or more other active ingredients and/or, for example, one ormore vitamins.

As usual, the dosage of the compounds of the formula I depends on thecircumstances of the specific case and is adjusted by the physicianaccording to the customary rules and procedures. It depends, forexample, on the compound of the formula I administered and its potencyand duration of action, on the nature and severity of the individualsyndrome, on the sex, age, weight and the individual responsiveness ofthe human or animal to be treated, on whether the treatment is acute orchronic or prophylactic, or on whether further pharmaceutical activecompounds are administered in addition to compound of the formula I.Normally, in the case of administration to an adult weighing about 75kg, a dose of from about 0.1 mg to about 100 mg per kg per day,preferably from about 1 mg to about 10 mg per kg per day (in each casein mg per kg of body weight), is sufficient. The daily dose can beadministered in the form of a single dose or divided into a number ofindividual doses, for example two, three or four individual doses. Theadministration can also be carried out continuously, for example bycontinuous injection or infusion. Depending on the circumstances of thespecific case, it may be necessary to deviate upward or downward fromthe indicated dosages.

Besides as a pharmaceutical active compound in human medicine andveterinary medicine, the compounds of the formula I can also be employedas an aid in biochemical investigations or as a scientific tool or fordiagnostic purposes, for example in in vitro diagnoses of biologicalsamples, if an inhibition of renin is intended. The compounds of theformula I and their salts can also be used as intermediates, for examplefor the preparation of further pharmaceutical active substances.

The following examples illustrate the invention.

Abbreviations:

ACN acetonitrileB-OM-9-BBN B-methoxy-9-borabicyclo[3.3.1]nonaneDCM dichloromethaneDMF dimethylformamideDMSO dimethyl sulfoxideEA ethyl acetateEDC N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochlorideHEP n-heptaneHOAT 1-hydroxy-7-azabenzotriazoleMOH methanol

NMM N-methyl-morpholine NMP N-methyl-pyrrolidin-2-one

S-PHOS 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenylTFA trifluoroacetic acidTHF tetrahydrofuran

When compounds containing a basic group were purified by preparativehigh pressure liquid chromatography (HPLC) on reversed phase (RP) columnmaterial and, as customary, the eluent was a gradient mixture of waterand acetonitrile containing trifluoroacetic acid, they were in generalobtained in the form of an acid addition salt with trifluoroacetic acid,depending on the details of the workup such as the lyophilizationconditions. Such contained trifluoroacetic acid, whose amount can varyand can be up to about two equivalents of acid in the case of a compoundcontaining two basic groups, for example, is not specified in the namesin the headings of the examples and not depicted in the structuralformulae, but indicated in the description of the examples. This appliesaccordingly to compounds which were obtained in the form of another acidaddition salt such as an acid addition salt with hydrochloric acid,whose amount can likewise vary and can be up to about two equivalents ofacid in the case of a compound containing two basic groups, for example,and which is not specified in the names in the headings of the examplesand not depicted in the structural formulae, but indicated in thedescription of the examples. The particulars of the preparative HPLCmethod were as follows. Column: Waters Atlantis dC18 OBD, 30×100 mm, 5μm. Flow: 60 ml/min. Eluent A: ACN. Eluent B: water+0.1% TFA. Gradient:from 10% A+90% B to 90% A+10% B within 10 min.

Characterization of the Compounds

The prepared compounds were in general characterized by spectroscopicdata and chromatographic data, in particular mass spectra (MS) and HPLCretention times (Rt; in min) which were obtained by combined analyticalHPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance(NMR) spectra. Unless specified otherwise, ¹H-NMR spectra were recordedat 500 MHz and in DMSO-D₆ as solvent. In the NMR characterization, thechemical shift δ (in ppm), the number of hydrogen atoms and themultiplicity (s: singlet, d: doublet, dd: double doublet, t: triplet,dt: double triplet, q: quartet, m: multiplet; br: broad) of the peaksare given. In the MS characterization, in general the mass number (m/z)of the peak of the molecular ion (M, e.g. M⁺) or of a related ion suchas the ion M+1 (e.g. M+1⁺; protonated molecular ion M+H⁺) or the ionM−17 (e.g. M−17⁺; protonated molecular ion minus H₂O), which was formeddepending on the ionization method used, is given. Generally, theionization method was electrospray ionization (ESI). The particulars ofthe LC/MS methods used were as follows.

Method LC1

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; MS ionizationmethod: ESI⁺

Method LC2

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: from 5% A+95% B to95% A+5% B within 3.4 min, then 95% A+5% B for 1.0 min; MS ionizationmethod: ESI⁺

Method LC3

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.08% formic acid; eluent B: water+0.1% formic acid; gradient: from5% A+95% B to 95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; MSionization method: ESI⁺

Method LC4

Column: YMC J'sphere ODS H80, 20×2.1 mm, 4 μm; flow: 1.0 ml/min; eluentA: ACN; eluent B: water+0.05% TFA; gradient: from 4% A+96% B to 95% A+5%B within 2.0 min, then 95% A+5% B for 0.4 min, then to 96% A+4% B within0.05 min; MS ionization method: ESI⁺

Method LC5

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1.3 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% B for 0.5min, then to 95% A+5% B within 3.0 min, then 95% A+5% B for 0.5 min; MSionization method: ESI⁺

Method LC6

Column: YMC J'sphere H80, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 2% A+98% B for 1min, then to 95% A+5% B within 4 min, then 95% A+5% B for 1.25 min; MSionization method: ESI⁺

Method LC7

Column: YMC Pack Pro C18 RS, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; eluentA: ACN+0.1% TFA; eluent B: water+0.1% TFA; gradient: from 5% A+95% B to95% A+5% B within 2.5 min, then 95% A+5% B for 0.5 min; MS ionizationmethod: ESI⁺

Method LC8

Column: Waters XBridge C18, 33'2.1 mm, 4 μm; flow: 1.0 ml/min; eluent A:ACN+0.05% TFA; eluent B: water+0.05% TFA; gradient: 5% A+95% B for 0.3min, then to 95% A+5% B within 3.2 min, then 95% A+5% B for 0.5 min; MSionization method: ESI⁺

Method LC9

Column: Waters XBridge C18, 33×2.1 mm, 4 μm; flow: 1.0 ml/min; eluent A:ACN+0.1% TFA; eluent B: water+0.08% TFA; gradient: from 3% A+97% B to60% A+40% B within 3.5 min, then to 98% A+2% B within 1.5 min; MSionization method: ESI⁺

Example 1[2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-(2-Chloro-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylic acidtert-butyl ester

To a solution of 2-chloro-1-phenyl-1H-indole-3-carboxylic acid (cf. CA1079739) (3.00 g, 11.0 mmol), tert-butyl 1-piperazinecarboxylate (2.06g, 11.0 mmol), EDC (2.33 g, 12.1 mmol) and HOAT (1.73 g, 12.7 mmol) inDMF (12 ml) was added NMM (3.65 ml, 33.1 mmol), and the reaction mixturewas stirred at room temperature overnight. The mixture was quenched withwater and extracted with EA. The organic layer was separated, dried oversodium sulfate, filtered, and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (EA/HEP 1:3). 4.51 gof the title compound were obtained.

LC/MS (method LC4): m/z=440

Step 2:4-[2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 5-fluoro-2-methylphenol (43.0 mg, 341 μmol) in NMP (1.5ml) was added sodium hydride (15.0 mg, 375 μmol; 60% dispersion inmineral oil), and the suspension was stirred at room temperature underan argon atmosphere for 20 min. After addition of 50.0 mg (114 μmol) ofthe compound of step 1, the reaction mixture was stirred for 2 h at 150°C. in a microwave reactor. The mixture was filtered and purified bypreparative HPLC. The eluate was lyophilized overnight to give 23 mg ofthe title compound.

LC/MS (method LC4): m/z=530

Step 3:[2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

A solution of the compound of step 2 (23 mg, 43.4 μmol) in DCM (8 ml)and TFA (2 ml) was stirred at room temperature for 1 h. The solventswere evaporated and the resulting solid dissolved in MOH and water andlyophilized overnight. The title compound was obtained in the form ofthe[2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt as a white solid. Yield: 21.0 mg.

LC/MS (method LC2): m/z=430.25, Rt=1.60 min

¹H-NMR: δ (ppm)=2.10 (s, 3H), 3.02 (br s, 4H), 3.68 (br s, 4H),6.77-6.84 (m, 2H), 7.17-7.21 (m, 2H), 7.22-7.28 (m, 2H), 7.45-7.49 (m,1H), 7.51-7.57 (m, 4H), 7.65-7.67 (m, 1H), 8.79 (br s, 2H)

Example 2[1-Phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[1-Phenyl-2-(2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 1,step 2, using 2-methylphenol. Yield: 40 mg.

LC/MS (method LC4): m/z=512

Step 2:[1-Phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (40.0 mg, 78.2 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the[1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 41.0 mg.

LC/MS (method LC1): m/z=411.19, Rt=1.40 min

¹H-NMR: δ (ppm)=2.14 (s, 3H), 2.98 (br s, 4H), 3.65 (br s, 4H), 6.82 (d,1H), 6.95 (t, 1H), 7.05 (t, 1H), 7.15 (d, 1H), 7.17-7.55 (m, 3H),7.44-7.55 (m, 5H), 7.65 (d, 1H), 8.77 (br s, 2H)

Example 3[2-(Methyl-phenyl-amino)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[2-(Methyl-phenyl-amino)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 1,step 2, using N-methylaniline. Yield: 6 mg.

LC/MS (method LC4): m/z=511

Step 2:[2-(Methyl-phenyl-amino)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (6 mg, 11.7 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the[2-(methyl-phenyl-amino)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 6 mg.

LC/MS (method LC1): m/z=410.21, Rt=1.40 min

¹H-NMR: δ (ppm)=2.95 (br s, 4H), 3.06 (s, 3H), 3.60 (br s, 4H),6.70-6.74 (m, 3H), 7.11 (t, 2H), 7.17-7.19 (m, 1H), 7.21-7.25 (m, 2H),7.41-7.45 (m, 3H), 7.51 (t, 2H), 7.61-7.63 (m, 1H), 8.75 (br s, 2H)

Example 4[2-(2-Chloro-phenylsulfanyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[2-(2-Chloro-phenylsulfanyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 1,step 2, using 2-chlorothiophenol. Yield: 32 mg.

LC/MS (method LC4): m/z=549

Step 2:[2-(2-Chloro-phenylsulfanyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (32.0 mg, 58.4 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the[2-(2-chloro-phenylsulfanyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 30 mg.

LC/MS (method LC1): m/z=447.12, Rt=1.48 min

¹H-NMR: δ (ppm)=3.04 (br s, 2H), 3.18 (br s, 2H), 3.64 (br s, 2H), 3.76(br s, 2H), 6.77-6.80 (m, 1H), 7.12-7.16 (m, 3H), 7.27-7.37 (m, 5H),7.46-7.50 (m, 3H), 7.73 (d, 1H), 8.80 (br d, 2H)

Example 5Perhydro-1,4-diazepin-1-yl-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanone

Step 1:4-(2-Phenoxy-1-phenyl-1H-indole-3-carbonyl)-perhydro-1,4-diazepine-1-carboxylicacid tert-butyl ester

To a solution of 2-phenoxy-1-phenyl-1H-indole-3-carboxylic acid (164 mg,499 μmol; available by oxidation of2-phenoxy-1-phenyl-1H-indole-3-carbaldehyde (DE 2707268) analogously asdescribed in example 11, step 5), tert-butyl 1-homopiperazinecarboxylate(100 mg, 499 μmol), EDC (105 mg, 549 μmol) and HOAT (78.2 mg, 574 μmol)in DMF (2 ml) was added NMM (165 μl, 1.49 mmol) and the reaction mixturewas stirred at room temperature overnight. The mixture was filtered andpurified by preparative HPLC. The eluate was lyophilized overnight togive 169 mg of the title compound.

LC/MS (method LC4): m/z=512

Step 2:Perhydro-1,4-diazepin-1-yl-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanone

From the compound of step 1 (169 mg, 330 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of theperhydro-1,4-diazepin-1-yl-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanonetrifluoroacetic acid salt. Yield: 158 mg.

LC/MS (method LC3): m/z=411.19, Rt=1.51 min

¹H-NMR (400 MHz): δ (ppm)=1.92 (br s, 2H), 3.02 (br s, 2H), 3.11 (br s,2H), 3.60 (br s, 4H), 6.96 (d, 2H), 7.05 (t, 1H), 7.17-7.28 (m, 5H),7.43-7.56 (m, 5H), 7.64-7.67 (m, 1H), 8.68 (br s, 2H)

Example 6 (2-Phenoxy-1-phenyl-1H-indol-3-yl)-piperazin-1-yl-methanone

Step 1:4-(2-Phenoxy-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylic acidtert-butyl ester

The title compound was prepared analogously as described in example 1,step 1, using 2-phenoxy-1-phenyl-1H-indole-3-carboxylic acid (500 mg,1.52 mmol). Yield: 608 mg.

LC/MS (method LC4): m/z=498

Step 2: (2-Phenoxy-1-phenyl-1H-indol-3-yl)-piperazin-1-yl-methanone

From the compound of step 1 (48 mg, 96.4 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the(2-phenoxy-1-phenyl-1H-indol-3-yl)-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 39 mg.

LC/MS (method LC1): m/z=397.18, Rt=1.37 min

¹H-NMR: δ (ppm)=3.01 (s, 4H), 3.64 (s, 4H), 6.96 (d, 2H), 7.06 (t, 1H),7.19-7.29 (m, 5H), 7.44-7.56 (m, 5H), 7.66-7.68 (m, 1H), 8.77 (br s, 2H)

Example 7[6-Hydroxy-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 6-Methoxy-1-phenyl-1,3-dihydro-indol-2-one

To a mixture of 6-methoxy-1,3-dihydroindol-2-one (500 mg, 3.06 mmol),copper(I) iodide (58.3 mg, 306 μmol), N,N′-dimethylethylenediamine (65.3μl, 613 μmol) and potassium carbonate (932 mg, 6.74 mmol) in ACN (6.5ml) was added iodobenzene (411 μl, 3.68 mmol). The reaction mixture wasstirred for 1 h at 120° C. in a microwave reactor. The mixture wasquenched with water and extracted with EA. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel chromatography (EA/HEP 1:5). 550 mgof the title compound were obtained.

LC/MS (method LC4): m/z=240

Step 2: 2-Chloro-6-methoxy-1-phenyl-1H-indole-3-carbaldehyde

A solution of DMF (2.1 ml) and DCM (2.1 ml) was cooled to 0° C. andstirred under argon. Within 15 min phosphorus oxychloride (2.1 ml, 22.6mmol) was added and the reaction mixture was stirred for 30 min at 0° C.The compound of step 1 (550 mg, 2.30 mmol), dissolved in chloroform(5.27 ml) and pyridine (1.05 ml), was then added to the cooled solution.The reaction mixture was stirred at room temperature overnight. Themixture was slowly poured into 300 ml of ice, and after a few minutes EAwas added. The organic layer was separated, dried over sodium sulfate,filtered and evaporated under reduced pressure. Column chromatography onsilica gel (EA/HEP 1:4) yielded 369 mg of the title compound as a whitesolid.

LC/MS (method LC4): m/z=286

Step 3: 2-Chloro-6-methoxy-1-phenyl-1H-indole-3-carboxylic acid

The compound of step 2 (365 mg, 1.27 mmol) was dissolved in tert-butanol(15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite(1.06 g, 11.7 mmol) and sodium dihydrogenphosphate (1.06 g, 8.82 mmol)in water (6 ml) was added. The reaction mixture was stirred at roomtemperature for 48 h. The mixture was diluted with water and extractedwith EA. The organic layer was dried over sodium sulfate, filtered andthe solvent was removed under reduced pressure to give 394 mg of thecrude title compound.

LC/MS (method LC4): m/z=302

Step 4:4-(2-Chloro-6-methoxy-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3 (394 mg, 1.31 mmol), the title compound wasprepared analogously as described in example 1, step 1. Yield: 730 mg ofcrude product.

LC/MS (method LC4): m/z=470

Step 5:4-[6-Methoxy-1-phenyl-2-(2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 4, the title compound was prepared analogouslyas described in example 1, step 2, using 2-methylphenol. Yield: 480 mg.

LC/MS (method LC4): m/z=542

Step 6:[6-Hydroxy-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

A solution of boron tribromide (2.71 ml, 2.71 mmol, 1 M in DCM) wasadded dropwise at −78° C. to a solution of the compound of step 5 (245mg, 452 μmol) in DCM (10 ml). The cooling bath was removed and themixture was stirred at room temperature for 2 h. The solvent wasevaporated and the residue was purified by preparative HPLC. The eluatewas lyophilized overnight to give the title compound in the form of the[6-hydroxy-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 121 mg.

LC/MS (method LC1): m/z=427.19, Rt=1.24 min

¹H-NMR: δ (ppm)=2.11 (s, 3H), 2.98 (br s, 4H), 3.66 (br s, 4H), 6.55 (d,1H), 6.72-6.75 (m, 2H), 6.91 (t, 1H), 7.03 (dt, 1H), 7.12 (d, 1H),7.40-7.46 (m, 4H), 7.51 (t, 2H), 8.74 (br s, 2H), 9.26 (s, 1H)

Example 84-[6-Hydroxy-1-phenyl-2-(2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 111 mg (239 μmol) of the compound of example 7 in MOH(2.2 ml) and THF (2.2 ml) was added sodium hydrogencarbonate (40.2 mg,478 μmol) and a solution of di-tert-butyl dicarbonate (52.2 mg, 239μmol) in THF (4.4 ml). The reaction mixture was stirred at roomtemperature overnight. The solvents were evaporated and the resultingsolid was dissolved in water and EA. The organic layer was separated,dried over sodium sulfate, filtered, and evaporated under reducedpressure. The residue was purified by silica gel chromatography(EA/HEP). 63 mg of the title compound were obtained.

LC/MS (method LC4): m/z=528

Example 9[6-Chloro-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 2,6-Dichloro-1H-indole-3-carbaldehyde

The title compound was obtained from 6-chloro-1,3-dihydro-indol-2-one(2.00 g, 11.9 mmol) analogously as described in example 7, step 2.Yield: 596 mg.

LC/MS (method LC4): m/z=214

Step 2: 2,6-Dichloro-1-phenyl-1H-indole-3-carbaldehyde

To a suspension of 500 mg pulverized molecular sieve (4 Å), the compoundof step 1 (295 mg, 1.38 mmol), phenylboronic acid (336 mg, 2.76 mmol)and copper(II) acetate (500 mg, 2.76 mmol) in DCM (10 ml) was addedpyridine (223 μl, 2.76 mmol) and triethylamine (384 μl, 2.76 mmol). Thereaction mixture was stirred at room temperature for 4 days. The mixturewas diluted with water and extracted with DCM. The organic layer wasseparated, dried over sodium sulfate, filtered, evaporated under reducedpressure. The residue was purified by silica gel chromatography (EA/HEP1:4). 345 mg of the title compound were obtained.

LC/MS (method LC4): m/z=291

Step 3: 2,6-Dichloro-1-phenyl-1H-indole-3-carboxylic acid

From the compound of step 2 (345 mg, 1.19 mmol), the title compound wasprepared analogously as described in example 7, step 3. Yield: 370 mg ofcrude product.

LC/MS (method LC4): m/z=307

Step 4:4-(2,6-Dichloro-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3 (370 mg, 1.21 mmol), the title compound wasprepared analogously as described in example 1, step 1. Yield: 738 mg ofcrude product.

LC/MS (method LC4): m/z=475

Step 5:4-[6-Chloro-1-phenyl-2-(2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 4 (100 mg, 211 μmol), the title compound wasprepared analogously as described in example 1, step 2, using2-methylphenol. Yield: 29 mg.

LC/MS (method LC4): m/z=547

Step 6:[6-Chloro-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 5 (29.0 mg, 53.1 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the[6-chloro-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 23 mg.

LC/MS (method LC1): m/z=445.16, Rt=1.54 min

¹H-NMR: δ (ppm)=2.13 (s, 3H), 2.98 (br s, 4H), 3.63 (br s, 4H), 6.84 (d,1H), 6.96 (dt, 1H), 7.05 (dt, 1H), 7.14-7.16 (m, 2H), 7.28 (dd, 1H),7.46-7.56 (m, 5H), 7.66 (d, 1H), 8.75 (br s, 2H)

Example 10[2-(3-Fluoro-2-methyl-phenoxy)-1-thiophen-3-yl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 2-Chloro-1-thiophen-3-yl-1H-indole-3-carbaldehyde

The title compound was prepared analogously as described in example 9,step 2, using 2-chloro-1H-indole-3-carbaldehyde (300 mg, 1.67 mmol) andthiophene-3-boronic acid. Yield: 123 mg.

LC/MS (method LC4): m/z=262

Step 2: 2-Chloro-1-thiophen-3-yl-1H-indole-3-carboxylic acid

From the compound of step 1 (123 mg, 0.47 mmol), the title compound wasprepared analogously as described in example 7, step 3. Yield: 133 mg ofcrude product.

LC/MS (method LC4): m/z=278

Step 3:4-(2-Chloro-1-thiophen-3-yl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 2 (133 mg, 0.48 mmol), the title compound wasprepared analogously as described in example 1, step 1. Yield: 245 mg.

LC/MS (method LC4): m/z=446

Step 4:4-[2-(3-Fluoro-2-methyl-phenoxy)-1-thiophen-3-yl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3 (50 mg, 112 μmol), the title compound wasprepared analogously as described in example 1, step 2, using3-fluoro-2-methylphenol. Yield: 11 mg.

LC/MS (method LC4): m/z=536

Step 5:[2-(3-Fluoro-2-methyl-phenoxy)-1-thiophen-3-yl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 4 (10.0 mg, 18.7 μmol), the title compound wasprepared analogously as described in example 1, step 3, and obtained inthe form of the[2-(3-fluoro-2-methyl-phenoxy)-1-thiophen-3-yl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 13 mg.

LC/MS (method LC1): m/z=435.14; Rt=1.43 min

¹H-NMR: δ (ppm)=2.13 (s, 3H), 3.01 (br s, 4H), 3.65 (br s, 4H), 6.67 (d,1H), 6.91 (t, 1H), 7.09 (q, 1H), 7.23 (dd, 1H), 7.25-7.28 (m, 3H),7.64-7.66 (m, 1H), 7.71 (dd, 1H), 7.78 (dd, 1H), 8.74 (br s, 2H)

Example 11{2-(5-Fluoro-2-methyl-phenoxy)-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indol-3-yl}-piperazin-1-yl-methanone

Step 1 1-Iodo-2-(3-methoxy-propoxy)-benzene

To a stirred solution of 2-iodophenol (3.00 g, 13.6 mmol),3-methoxy-1-propanol (1.57 ml, 16.4 mmol) and triphenylphosphine (4.29g, 16.4 mmol) in THF (15 ml) was added dropwise diisopropylazodicarboxylate (3.22 ml, 16.4 mmol). The reaction mixture was stirredat room temperature overnight. The mixture was quenched with water andextracted with EA. The organic layer was separated, dried over sodiumsulfate, filtered, and evaporated under reduced pressure: The residuewas purified by silica gel chromatography (EA/HEP 1:5). 4.00 g of thetitle compound were obtained.

LC/MS (method LC4): m/z=293

Step 2: 1-[2-(3-Methoxy-propoxy)-phenyl]-1H-indole

A mixture of the compound of step 1 (8.00 g, 27.4 mmol), indole (3.21 g,27.4 mmol), copper(I) iodide (522 mg, 2.74 mmol), L-proline (636 mg,5.48 mmol) and potassium carbonate (7.68 g, 54.8 mmol) in DMSO (50 ml)was stirred for 26 h at 125° C. The mixture was quenched with water andextracted with EA. The organic layer was separated, dried over sodiumsulfate, filtered and evaporated. The residue was purified bypreparative HPLC. The eluate was lyophilized overnight to give 3.10 g ofthe title compound.

LC/MS (method LC4): m/z=282

Step 3: 1-[2-(3-Methoxy-propoxy)-phenyl]-1,3-dihydro-indol-2-one

The compound of step 2 (3.09 g, 11.0 mmol) was dissolved in DCM (83 ml),and N-chlorosuccinimide (1.54 g, 11.6 mmol) was added. The reactionmixture was stirred at room temperature for 2 h. The solvent wasremoved, the resulting solid was dissolved in concentrated acetic acid(45 ml) and heated to 70° C. After the addition of phosphoric acid (9.35ml, 137 mmol; 85%), the reaction mixture was heated to 120° C. for 2 h.The cooled mixture was diluted with water, extracted with EA, theorganic layer separated, dried over sodium sulfate, filtered, andevaporated. The residue was purified by silica gel chromatography(EA/HEP 1:6). 2.38 g of the title compound was obtained.

LC/MS (method LC4): m/z=298

Step 4:2-Chloro-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indole-3-carbaldehyde

From the compound of step 3 (1.62 g, 5.45 mmol), the title compound wasprepared analogously as described in example 7, step 2. Yield: 1.31 g.

LC/MS (method LC4): m/z=344

Step 5: 2-Chloro-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indole-3-carboxylicacid

To the compound of step 4 (100 mg, 2914 μmol) in a mixture of acetone(2.8 ml), water (1.36 ml) and a disodium hydrogenphosphate/potassiumdihydrogenphosphate buffer solution (2.0 ml; pH 7.0) was added withstirring at room temperature potassium permanganate (90.0 mg, 570 μmol)in small portions. After stirring at room temperature for 3 days, themixture was diluted with water and EA was added. The organic layer wasseparated, dried over sodium sulfate, filtered, and evaporated. Theresidue was purified by silica gel chromatography (EA/HEP 4:1). 50 mg ofthe title compound were obtained.

LC/MS (method LC4): m/z=342

Step 6:4-{2-Chloro-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indole-3-carbonyl}-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 200 mg (556 μmol) of the compound of step 5 in DMF (5ml) and NMM (122 μl, 1.11 mmol) was addedO-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (201 mg, 612 μmol), and the mixture was stirred atroom temperature for 30 min. tert-Butyl 1-piperazinecarboxylate (114 mg,612 μmol) was then added and the reaction mixture was stirred for 3 h.The mixture was quenched with water and extracted with EA. The organiclayer was separated, dried over sodium sulfate, filtered, andevaporated. The residue was purified by silica gel chromatography(EA/HEP 2:5). 285 mg of the title compound were obtained.

LC/MS (method LC4): m/z=529

Step 7:{2-(5-Fluoro-2-methyl-phenoxy)-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indol-3-yl}-piperazin-1-yl-methanone

The compound of step 6 (40.0 mg, 75.8 μmol) was reacted analogously asdescribed in example 1, step 2, using 5-fluoro-2-methylphenol andstirring the reaction mixture at 150° C. in a microwave reactor for 13h. The title compound was obtained in the form of the{2-(5-fluoro-2-methyl-phenoxy)-1-[2-(3-methoxy-propoxy)-phenyl]-1H-indol-3-yl}-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 3 mg.

LC/MS (method LC1): m/z=517.24; Rt=1.50 min

¹H-NMR: δ (ppm)=1.61-1.69 (m, 1H), 2.00 (s, 3H), 3.02 (s, 3H), 3.04 (d,2H), 3.07 (br s, 4H), 3.70 (br s, 4H), 3.86-3.90 (m, 1H), 3.92-3.97 (m,1H), 6.58 (dd, 1H), 6.79 (dt, 1H), 6.91 (d, 1H), 7.04 (t, 1H), 7.11-7.26(m, 4H), 7.40-7.45 (m, 2H), 7.67 (d, 1H), 8.76 (br s, 2H)

Example 12[6-(2-Methoxy-ethoxy)-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[6-(2-Methoxy-ethoxy)-1-phenyl-2-(2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The compound of example 8 (63.0 mg, 119 μmol) was dissolved in DMF, andcesium carbonate (116 mg, 358 μmol) and 2-bromoethyl methyl ether (13.5μl, 143 μmol) were added. The reaction mixture was stirred at 50° C. for3 h. The cooled mixture was diluted with water and extracted with EA.The organic layer was dried over sodium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (EA/HEP). 60.0 mg of the title compound were obtained.

LC/MS (method LC4): m/z=586

Step 2:[6-(2-Methoxy-ethoxy)-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (30.0 mg, 51.2 μmol), the title compound wasprepared analogously as described in example 1, step 3, and purified bysilica gel chromatography (EA/HEP). The obtained product was dissolvedin a small quantity of MOH, mixed with hydrochloric acid (0.1 M) andlyophilized overnight. 25.0 mg of the title compound were obtained inthe form of the[6-(2-methoxy-ethoxy)-1-phenyl-2-(2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride.

LC/MS (method LC2): m/z=485.23; Rt=1.52 min

¹H-NMR (400 MHz): δ (ppm)=2.12 (s, 3H), 2.96 (br s, 4H), 3.28 (s, 3H),3.61-3.63 (m, 2H), 3.68 (br s, 4H), 4.02-4.04 (m, 2H), 6.67 (d, 1H),6.74 (d, 1H), 6.89-6.94 (m, 2H), 7.04 (dt, 1H), 7.12 (d, 1H), 7.41-7.56(m, 6H), 9.10 (br s, 2H)

Example 13[2-(3-Fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 5-Methoxy-1-phenyl-1H-indole

To a mixture of 5-methoxyindole (1.00 g, 6.79 mmol), copper(I) iodide(129 mg, 0.68 mmol), L-proline (156 mg, 1.36 mmol) and potassiumcarbonate (1.88 g, 13.6 mmol) in DMSO (7.5 ml) was added iodobenzene(0.76 ml, 6.79 mmol). The reaction mixture was stirred for 10 h at 125°C. in a microwave reactor. The mixture was then quenched with water andextracted with EA. The organic layer was separated, dried over sodiumsulfate, filtered and evaporated. The residue was purified by silica gelchromatography (EA/HEP 1:15). 951 mg of the title compound wereobtained.

LC/MS (method LC4): m/z=224

Step 2: 5-Methoxy-1-phenyl-1,3-dihydro-indol-2-one

The compound of step 1 (800 mg, 3.58 mmol) was dissolved in DCM (25 ml),and N-chlorosuccinimide (526 mg, 3.94 mmol) was added. The reactionmixture was stir at room temperature overnight. The solvent was removed,the resulting solid was dissolved in concentrated acetic acid (15 ml)and heated to 70° C. After the addition of phosphoric acid (3.04 ml,44.6 mmol; 85%) the reaction mixture was heated to 130° C. for 2.5 h.The cooled mixture was diluted with water and extracted with EA. Theextracts were dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel chromatography (EA/HEP 1:3). 557 mgof the title compound were obtained.

LC/MS (method LC4): m/z=240

Step 3: 2-Chloro-5-methoxy-1-phenyl-1H-indole-3-carbaldehyde

A solution of DMF (2.3 ml) and DCM (2.3 ml) under argon was cooled to 0°C. With stirring, phosphorus oxychloride (2.14 ml, 22.9 mmol) was addedwithin 15 min, and the mixture was stirred for further 30 min at 0° C.Then the compound of step 2 (557 mg, 2.33 mmol), dissolved in chloroform(5.77 ml) and pyridine (1.15 ml), was added to the cooled solution. Thereaction mixture was stirred at room temperature overnight. The mixturewas slowly poured into 300 ml of ice and after a few minutes EA wasadded. The organic layer was separated, dried over sodium sulfate,filtered and evaporated under reduced pressure. Column chromatography ofthe residue on silica gel (EA/HEP 1:8) yielded 456 mg of the titlecompound as a white solid.

LC/MS (method LC4): m/z=286

Step 4: 2-Chloro-5-methoxy-1-phenyl-1H-indole-3-carboxylic acid

The compound of step 3 (456 mg, 1.59 mmol) was dissolved in tert-butanol(15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite(1.32 g, 14.6 mmol) and sodium dihydrogenphosphate (1.32 g, 11.0 mmol)in water (6 ml) was added. The reaction mixture was stirred at roomtemperature for 48 h and afterwards at 80° C. for 2.5 h. The mixture wasdiluted with water and extracted with EA. The organic layer was driedover sodium sulfate, filtered and the solvent was removed under reducedpressure to give 602 mg of the crude title compound.

LC/MS (method LC4): m/z=302

Step 5:4-(2-Chloro-5-methoxy-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 602 mg (1.99 mmol) of the compound of step 4,tert-butyl 1-piperazinecarboxylate (372 mg, 1.99 mmol), EDC (421 mg,2.19 mmol) and HOAT (312 mg, 2.29 mmol) in DMF (5 ml) was added NMM(0.66 ml, 5.98 mmol), and the reaction mixture was stirred at roomtemperature overnight. The mixture was quenched with water and extractedwith EA. The organic layer was separated, dried over sodium sulfate,filtered and evaporated to give 930 mg of the title compound.

LC/MS (method LC4): m/z=470

Step 6:4-[2-(3-Fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

To a suspension of zinc (322 mg, 4.92 mmol) in dry THF (770 μl) in a dryflask under argon was added 1,2-dibromoethane (10.6 μl, 0.123 mmol). Themixture was heated three times to reflux with a heat-gun. After 5 minthe flask was placed in an ice bath and a solution of3-fluoro-2-methyl-benzylbromide (500 mg, 2.46 mmol) in dry THF (1.5 ml)was added slowly, so that the temperature remained at 0° C. The mixturewas stirred at 0° C. for 3 h. The cooled suspension was added dropwiseto a precooled solution (−78° C.) of B-OM-9-BBN (2.45 ml, 2.45 mmol, 1 Min hexane). The mixture was then stirred at room temperature for 30 min.DMF (7 ml) was added, followed by the compound of step 5 (115 mg, 245μmol), palladium(II) acetate (5.49 mg, 24.5 μmol) and S—PHOS (20.1 mg,48.9 μmol). The reaction mixture was stirred at 100° C. for 2 h. Thecooled mixture was quenched with water and extracted with EA. Theorganic layer was separated, dried over sodium sulfate, filtered, andevaporated under reduced pressure. The residue was purified bypreparative HPLC. The eluate was lyophilized overnight to give 72 mg ofthe title compound.

LC/MS (method LC4): m/z=558

Step 7:[2-(3-Fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

To a solution of the compound of step 6 (72.0 mg, 129 μmol) in DCM (8ml) was added TFA (2 ml), and the reaction mixture was stirred at roomtemperature for 2 h. The solvents were evaporated. The solid wasdissolved in MOH and water and lyophilized to give the title compound inthe form of the[2-(3-fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt as a white solid. Yield: 70.0 mg.

LC/MS (method LC2): m/z=457.22; Rt=1.65 min

¹H-NMR: δ (ppm)=1.84 (s, 3H), 2.91 (br s, 2H), 3.21 (br s, 2H), 3.52 (brs, 2H), 3.73 (br s, 2H), 3.80 (s, 3H), 4.11 (s, 2H), 6.63 (d, 1H), 6.81(dd, 1H), 6.88-6.92 (m, 2H), 6.99 (q, 1H), 7.04 (d, 1H), 7.27 (dd, 2H),7.48-7.52 (m, 3H), 8.78 (br s, 2H)

Example 14[2-(3-Fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-methoxy-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 1-(4-Fluoro-phenyl)-6-methoxy-1,3-dihydro-indol-2-one

To a mixture of 6-methoxy-1,3-dihydro-indol-2-one (500 mg, 3.06 mmol),copper(I) iodide (58.3 mg, 306 μmol), N,N′-dimethylethylenediamine (65.3μl, 613 μmol) and potassium carbonate (932 mg, 6.74 mmol) in ACN (7 ml)was added 4-fluoroiodobenzene (474 μl, 3.68 mmol). The reaction mixturewas stirred for 3 h at 120° C. in a microwave reactor. The mixture wasquenched with water and extracted with EA. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel chromatography (EA/HEP 1:4). 510 mgof the title compound were obtained.

LC/MS (method LC4): m/z=258

Step 2: 2-Chloro-1-(4-fluoro-phenyl)-6-methoxy-1H-indole-3-carbaldehyde

From the compound of step 1 (505 mg, 1.96 mmol), the title compound wasprepared analogously as described in example 13, step 3. Yield: 286 mg.

LC/MS (method LC4): m/z=304

Step 3: 2-Chloro-1-(4-fluoro-phenyl)-6-methoxy-1H-indole-3-carboxylicacid

From the compound of step 2 (286 mg, 942 μmol), the title compound wasprepared analogously as described in example 13, step 4. Yield: 325 mgof crude product.

LC/MS (method LC4): m/z=320

Step 4:4-[2-Chloro-1-(4-fluoro-phenyl)-6-methoxy-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3 (325 mg, 1.02 mmol), the title compound wasprepared analogously as described in example 13, step 5. Yield: 479 mg.

LC/MS (method LC4): m/z=488

Step 5:4-[2-(3-Fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-methoxy-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 4 (80.0 mg, 164 μmol), the title compound wasprepared analogously as described in example 13, step 6. Yield: 49 mg.

LC/MS (method LC4): m/z=576

Step 6:[2-(3-Fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-methoxy-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 5 (49.0 mg, 85.1 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[2-(3-fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-methoxy-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 46 mg.

LC/MS (method LC1): m/z=475.21; Rt=1.44 min

¹H-NMR: δ (ppm)=1.86 (s, 3H), 2.94 (br s, 2H), 3.19 (br s, 2H), 3.57 (brs, 2H), 3.66 (s, 3H), 3.70 (br s, 2H), 4.07 (s, 2H), 6.43 (d, 1H), 6.61(d, 1H), 6.86 (dd, 1H), 6.90 (t, 1H), 6.98 (q, 1H), 7.31-7.33 (m, 4H),7.50 (d, 1H), 8.78 (br d, 2H)

Example 15[1-[2-(2-Methoxy-ethoxy)-phenyl]-2-(2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 1-Iodo-2-(2-methoxy-ethoxy)-benzene

To a mixture of 2-iodophenol (5.00 g, 22.7 mmol) and potassium carbonate(4.71 g, 34.1 mmol) in ACN (7 ml) was added 2-bromoethyl methyl ether(3.79 g, 27.3 mmol).

The reaction mixture was stirred for 2 h at 110° C. in a microwavereactor. The cooled mixture was quenched with water and extracted withEA. The organic layer was separated, washed with brine, dried oversodium sulfate, filtered, and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (EA/HEP 1:4). 4.59 gof the title compound were obtained.

LC/MS (method LC4): m/z=288

Step 2: 2-(2-methoxy-ethoxy)-phenylboronic acid

To a solution of the compound of step 1 (2.20 g, 7.91 mmol) in toluene(20 ml) and THF (4 ml) was added triisopropyl borate (2.19 ml, 9.49mmol), and the mixture was cooled to −78° C. n-Butyllithium (3.79 ml,9.49 mmol, 2.5 M in hexane) was added dropwise and the reaction mixturewas stirred at −78° C. for 1.5 h. The cooling bath was removed and thereaction mixture was allowed to warm to −20° C. Then 2 N hydrochloricacid (7 ml) was added. When the mixture had reached room temperature,water and EA were added. The organic layer was separated, dried oversodium sulfate, filtered and evaporated in vacuo. The residue waspurified by silica gel chromatography (EA/HEP 1:4). 766 mg of the titlecompound were obtained.

LC/MS (method LC4): m/z=179

Step 3:2-Chloro-1-[2-(2-methoxy-ethoxy)-phenyl]-1H-indole-3-carbaldehyde

To a suspension of 500 mg pulverized molecular sieves (4 Å), thecompound of step 2 (761 mg, 3.88 mmol),2-chloro-1H-indole-3-carbaldehyde (465 mg, 2.59 mmol) and copper(II)acetate (940 mg, 5.18 mmol) in DCM (20 ml) was added pyridine (0.42 ml,5.18 mmol) and triethylamine (0.72 ml, 5.18 mmol). The reaction mixturewas stirred at room temperature for one week. The mixture was dilutedwith water and extracted with DCM. The organic layer was separated,dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was purified by preparative HPLC. The eluate waslyophilized overnight to give 56 mg of the title compound.

LC/MS (method LC4): m/z=330

Step 4: 2-Chloro-1-[2-(2-methoxy-ethoxy)phenyl]-1H-indole-3-carboxylicacid

From the compound of step 3 (100 mg, 303 μmol), the title compound wasprepared analogously as described in example 13, step 4. Yield: 150 mgof crude product.

LC/MS (method LC4): m/z=328

Step 5:4-{2-Chloro-1-[2-(2-methoxy-ethoxy)-phenyl]-1H-indole-3-carbonyl}-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 4 (150 mg, 434 μmol), the title compound wasprepared analogously as described in example 13, step 5. Yield: 207 mg.

LC/MS (method LC4): m/z=514

Step 6:4-[1-[2-(2-Methoxy-ethoxy)-phenyl]-2-(2-methyl-benzyl)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

A solution of 2-methylbenzylzinc chloride (1.95 ml, 973 μmol, 0.5 M inTHF) was added dropwise at −78° C. to a solution of B-OM-9-BBN (0.97 ml,973 μmol, 1 M in hexane). The cooling bath was removed and the mixturewas stirred at room temperature for 30 min. DMF (2 ml) was added,followed by the compound of step 5 (50 mg, 97.3 μmol), palladium(II)acetate (2.18 mg, 9.73 μmol) and S-PHOS (7.99 mg, 19.5 μmol). Thereaction mixture was heated to 100° C. and stirred for 4 h. The mixturewas diluted with water and extracted with EA. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was purified by preparative HPLC. Theeluate was lyophilized overnight to give 14 mg of the title compound.

LC/MS (method LC4): m/z=584

Step 7:[1-[2-(2-Methoxy-ethoxy)-phenyl]-2-(2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 6 (11.0 mg, 18.8 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[1-[2-(2-methoxy-ethoxy)-phenyl]-2-(2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 17 mg.

LC/MS (method LC1): m/z=483.25; Rt=1.40 min

¹H-NMR: δ (ppm)=1.92 (s, 3H), 2.88 (br s, 2H), 3.04 (s, 3H), 3.17 (br s,2H), 3.68 (br s, 2H), 3.90 (br d, 1H), 3.94-3.98 (m, 1H), 4.01-4.06 (m,1H), 4.12 (br d, 1H), 6.79 (d, 1H), 6.86 (d, 1H), 6.91-7.03 (m, 4H),7.10-7.19 (m, 3H), 7.22 (d, 1H), 7.44-7.48 (m, 1H), 7.56 (d, 1H), 8.75(br d, 2H)

Example 16[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-(2-Chloro-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylic acidtert-butyl ester

The title compound was prepared from2-chloro-1-phenyl-1H-indole-3-carboxylic acid (cf. CA 1079739) (3.00 g,11.0 mmol) analogously as described in example 13, step 5.

After purification by silica gel chromatography (EA/HEP 1:3), 4.51 g ofthe title compound were obtained.

LC/MS (method LC4): m/z=440

Step 2:4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 1 (150 mg, 0.34 mmol), the title compound wasprepared analogously as described in example 13, step 6. Yield: 126 mg.

LC/MS (method LC4): m/z=528

Step 3:[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 2 (126 mg, 239 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 130 mg.

LC/MS (method LC1): m/z=427.21; Rt=1.47 min

¹H-NMR: δ (ppm)=1.84 (s, 3H), 2.91 (br s, 2H), 3.20 (br s, 2H), 4.13 (s,2H), 6.65 (d, 1H), 6.90 (t, 1H), 6.96-7.01 (m, 2H), 7.17 (t, 1H), 7.22(t, 1H), 7.27-7.29 (m, 2H), 7.49-7.52 (m, 3H), 7.61 (d, 2H), 8.78 (br d,2H)

Example 17[2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

A solution of 500 mg (1.14 mmol) of the compound of example 16, step 1,in THF (8 ml) was cooled to −78° C. with an acetone/dry ice bath. Within10 min a solution of n-butyllithium (0.55 ml, 1.36 mmol, 2.5 M inhexane) was added followed by 0.36 ml (2.27 mmol) of2-chloro-6-fluoro-benzyl bromide. The cooling bath was removed and thereaction mixture was allowed to warm up slowly to room temperature andstirred overnight. The mixture was quenched with water and extractedwith EA. The organic layer was separated, dried over sodium sulfate,filtered, and evaporated under reduced pressure. The residue waspurified by preparative HPLC. The eluate was lyophilized overnight togive 216 mg of the title compound.

LC/MS (method LC4): m/z=549

Step 2:[2-(2-Chloro-6-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (216 mg, 394 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[2-(2-chloro-6-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 217 mg.

LC/MS (method LC2): m/z=447.15; Rt=1.60 min

¹H-NMR: δ (ppm)=2.89 (br s, 2H), 3.15 (br s, 2H), 3.68 (br s, 2H), 4.21(br s, 2H), 6.98 (dd, 1H), 7.02-7.07 (m, 1H), 7.12-7.27 (m, 4H), 7.41(br d, 2H), 7.53-7.59 (m, 4H), 8.85 (br s, 2H)

Example 18[2-(5-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[2-(5-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of example 16, step 1, (150 mg, 341 μmol) the titlecompound was prepared analogously as described in example 17, step 1,using 5-fluoro-2-methylbenzyl bromide. Yield: 9 mg.

LC/MS (method LC4): m/z=528

Step 2:[2-(5-Fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (9 mg, 17.1 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[2-(5-fluoro-2-methyl-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 8 mg.

LC/MS (method LC1): m/z=427.21; Rt=1.47 min

¹H-NMR: δ (ppm)=1.87 (s, 3H), 2.95 (br s, 2H), 3.22 (br s, 2H), 3.58 (brs, 2H), 3.74 (br s, 2H), 4.08 (s, 2H), 6.60 (dd, 1H), 6.84 (dt, 1H),6.98-7.03 (m, 2H), 7.16-7.29 (m, 4H), 7.50-7.52 (m, 3H), 7.62 (d, 1H),8.80 (br d, 2H)

Example 19[2-(2-Chloro-5-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[2-(2-Chloro-5-fluoro-benzyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

To a suspension of zinc (176 mg, 2.69 mmol) in dry THF (1 ml) in a dryflask under argon was added 1,2-dibromoethane (5.79 μl, 67.2 μmol). Themixture was heated three times to reflux with a heat-gun. After 5 minthe flask was placed in an ice bath and a solution of2-chloro-5-fluoro-benzylbromide (182 μl, 1.34 mmol) in dry THF (1.5 ml)was added slowly, so that the temperature remained at 0° C. The mixturewas stirred at 0° C. for 3 h. Then the cooled suspension was addeddropwise to a precooled solution (0° C.) of the compound of example 16,step 1 (59.0 mg, 134 μmol), nickel acetylacetonate (3.44 mg, 13.4 μmol)and tetrabutylammonium iodide (149 mg, 402 μmol) in THF (4 ml) and NMP(2 ml). The reaction mixture was stirred at 0° C. for 3 h and then atroom temperature for 48 h. The mixture was quenched with water andextracted with EA. The organic layer was separated, dried over sodiumsulfate, filtered, and evaporated under reduced pressure. The residuewas purified by preparative HPLC. The eluate was lyophilized overnightto give 17 mg of the title compound.

LC/MS (method LC4): m/z=549

Step 2:[2-(2-Chloro-5-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (17 mg, 31 μmol), the title compound wasprepared analogously as described in example 13, step 7, and obtained inthe form of the[2-(2-chloro-5-fluoro-benzyl)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 16 mg.

LC/MS (method LC1): m/z=447.15; Rt=1.46 min

¹H-NMR: δ (ppm)=3.02 (br s, 2H), 3.22 (br s, 2H), 3.57 (br s, 2H), 3.75(br s, 2H), 4.22 (s, 2H), 6.80 (dd, 1H), 7.00 (d, 1H), 7.05 (dt, 1H),7.17-7.25 (m, 2H), 7.29-7.33 (m, 3H), 7.50-7.55 (m, 3H), 7.63 (d, 1H),8.81 (br d, 2H)

Example 20[2-(3-Fluoro-2-methyl-benzyl)-5-hydroxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

A solution of boron tribromide (87.5 μl, 87.5 μmol, 1 M in DCM) wasadded dropwise at −78° C. to a solution of the compound of example 13(25.0 mg, 43.7 μmol) in DCM (1 ml). The cooling bath was removed and themixture was stirred at room temperature overnight. The solvent wasevaporated and the resulting solid was purified by preparative HPLC. Theeluate was lyophilized overnight to give the title compound in the formof the[2-(3-fluoro-2-methyl-benzyl)-5-hydroxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt. Yield: 9 mg.

LC/MS (method LC1): m/z=443.20; Rt=1.37 min

¹H-NMR: δ (ppm)=1.84 (s, 3H), 2.90 (br s, 2H), 3.17 (br s, 2H), 3.58 (brs, 2H), 3.68 (br s, 2H), 4.10 (s, 2H), 6.62 (d, 1H), 6.67 (dd, 1H), 6.81(d, 1H), 6.87-6.92 (m, 2H), 6.98 (q, 2H), 7.25 (d, 2H), 7.46-7.51 (m,3H), 8.81 (br d, 2H), 9.10 (s, 1H)

Example 21[2-(3-Fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-hydroxy-1H-indol-3-yl]-piperazin-1-yl-methanone

A solution of boron tribromide (153 μl, 153 μmol, 1 M in DCM) was addeddropwise at −78° C. to a solution of the compound of example 14 (30.0mg, 50.9 μmol) in DCM (1 ml). The cooling bath was removed and thereaction mixture was stirred at room temperature overnight. The mixturewas again cooled to −78° C. and boron tribromide was added (153 μl, 153μmol, 1 M in DCM). The reaction mixture was stirred at room temperaturefor 3 h. Then the solvent was evaporated and the resulting solid waspurified by silica gel chromatography (DCM/MOH 10:1+2% aqueous ammonia).The eluate was evaporated, the residue dissolved in a small quantity ofMOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight togive 18.0 mg of the title compound in the form of the[2-(3-fluoro-2-methyl-benzyl)-1-(4-fluoro-phenyl)-6-hydroxy-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride.

LC/MS (method LC3): m/z=461.19; Rt=1.46 min

¹H-NMR: δ (ppm)=1.86 (s, 3H), 3.93 (br s, 2H), 3.16 (br s, 2H), 3.62 (brs, 2H), 3.71 (br s, 2H), 4.06 (s, 2H), 6.31 (d, 1H), 6.61 (d, 1H); 6.72(dd, 1H), 6.89 (t, 1H), 6.98 (q, 1H), 7.28-7.32 (m, 4H), 7.38 (d, 1H),9.12 (br s, 2H), 9.21 (s, 1H)

Example 22[1-Cyclohex-2-enyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 2-Chloro-1-cyclohex-2-enyl-1H-indole-3-carbaldehyde

To a solution of 2-chloro-1H-indole-3-carbaldehyde (2.00 g, 11.1 mmol)in DMF (15 ml) was added sodium hydride (468 mg, 11.7 mmol, 60%dispersion in mineral oil). Under an argon atmosphere, the suspensionwas stirred at 40° C. for 20 min and then allowed to cool to roomtemperature. After the addition of 3-bromocyclohexene (2.56 ml, 22.3mmol) the reaction mixture was stirred at room temperature for 1 h. Themixture was then quenched with water and extracted with EA. The organiclayer was separated, dried over sodium sulfate, filtered and evaporated.The residue was and purified by silica gel chromatography (EA/HEP 1:10).1.13 g of the title compound were obtained.

LC/MS (method LC4): m/z=260

Step 2: 2-Chloro-1-cyclohex-2-enyl-1H-indole-3-carboxylic acid

From the compound of step 1 (1.13 g, 4.35 mmol), the title compound wasprepared analogously as described in example 7, step 3. Yield: 1.61 g ofcrude product.

LC/MS (method LC4): m/z=276

Step 3:4-(2-Chloro-1-cyclohex-2-enyl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

From the crude compound of step 2 (1.61 g), the title compound wasprepared analogously as described in example 1, step 1. Yield: 738 mg.

LC/MS (method LC4). m/z=444

Step 4:4-[1-Cyclohex-2-enyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3 (170 mg, 1.35 mmol), the title compound wasprepared as described in example 1, step 2. The mixture was quenchedwith water and extracted with EA. The organic layer was separated, driedover sodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (EA/HEP). Yield: 108mg.

LC/MS (method LC4): m/z=534

Step 5:[1-Cyclohex-2-enyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

The compound of step 4 (42.0 mg, 78.7 μmol) was reacted analogously asdescribed in example 1, step 3. The obtained solid was purified bypreparative HPLC, the eluate lyophilized overnight, the residuedissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1M) and lyophilized overnight. 24.0 mg of the title compound wereobtained in the form of the[1-cyclohex-2-enyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride.

LC/MS (method LC5): m/z=433.22; Rt=2.11 min

¹H-NMR: δ (ppm)=1.68-1.76 (m, 1H), 1.85-1.88 (m, 1H), 1.93-1.97 (m, 1H),2.01-2.18 (m, 3H), 2.32 (s, 3H), 2.94 (br s, 4H), 3.59 (br s, 4H), 5.15(br s, 1H), 5.71 (d, 1H), 5.93-5.97 (m, 1H), 6.66 (dd, 1H), 6.89 (dt,1H), 7.16-7.22 (m, 2H), 7.33 (t, 1H), 7.53-7.59 (m, 2H), 9.04 (br d, 2H)

Example 23[1-Cyclohexyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[1-Cyclohexyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The compound of example 22, step 4 (66.0 mg, 124 μmol) was dissolved inethanol (5 ml), and palladium on activated carbon (20 mg, 10%) wasadded. The mixture was hydrogenated overnight at room temperature and ahydrogen pressure of 4.5 bar. The mixture was filtered over celite andevaporated under reduced pressure to give 65.0 mg of the crude titlecompound.

LC/MS (method LC4): m/z=536

Step 2:[1-Cyclohexyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanone

The compound of step 1 (65.0 mg, 121 μmol) was reacted analogously asdescribed in example 1, step 3. The obtained solid was purified bypreparative HPLC, the eluate lyophilized overnight, the residuedissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1M) and lyophilized overnight. 43.6 mg of the title compound wereobtained in the form of the[1-cyclohexyl-2-(5-fluoro-2-methyl-phenoxy)-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride.

LC/MS (method LC6): m/z=435.23; Rt=3.04 min

¹H-NMR (400 MHz): δ (ppm)=1.22 (br t, 1H), 1.40 (br q, 2H), 1.66 (br d,1H), 1.83 (br t, 4H), 2.07 (br q, 2H), 2.36 (s, 3H), 2.92 (br s, 4H),3.58 (br s, 4H), 4.34-4.41 (m, 1H), 6.66 (dd, 1H), 6.90 (dt, 1H),7.15-7.24 (m, 2H), 7.35 (t, 1H), 7.51 (d, 1H), 7.71 (d, 1H), 9.11 (br s,2H)

Example 24(3-Hydroxymethyl-piperazin-1-yl)-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanone

Step 1:4-(2-Phenoxy-1-phenyl-1H-indole-3-carbonyl)-piperazine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester

The title compound was prepared from2-phenoxy-1-phenyl-1H-indole-3-carboxylic acid (420 mg, 1.28 mmol)analogously as described in example 1, step 1. Yield: 564 mg.

LC/MS (method LC4): m/z=556

Step 2:(3-Hydroxymethyl-piperazin-1-yl)-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanone

The compound of step 1 (100 mg, 0.18 mmol) was dissolved in THF (3.6ml), lithium borohydride (11.8 mg, 0.54 mmol) was added, and thereaction was stirred at room temperature for 2 h. The mixture waspartitioned between a saturated ammonium chloride solution and EA. Theorganic phase was washed with a saturated sodium hydrogencarbonatesolution and water, dried over sodium sulfate and evaporated underreduced pressure. The residue was dissolved in DCM (20 ml), TFA (5 ml)was added, and the mixture was stirred at room temperature for 1 h. Thesolvents were evaporated and the obtained solid was purified bypreparative HPLC. The eluate was lyophilized overnight, the residuedissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1M) and lyophilized overnight. 53 mg of the title compound were obtainedin the form of the(3-hydroxymethyl-piperazin-1-yl)-(2-phenoxy-1-phenyl-1H-indol-3-yl)-methanonehydrochloride.

LC/MS (method LC5): m/z=427.19; Rt=1.92 min

¹H-NMR: δ (ppm)=2.80 (m, 1H), 3.03 (m, 2H), 3.20 (m, 2H), 3.52 (m, 1H),3.59 (m, 1H), 4.17 (m, 2H), 4.95 (m, 1H), 6.96 (m, 2H), 7.07 (m, 1H),7.19-7.31 (m, 5H), 7.47 (m, 1H), 7.50-7.58 (m, 4H), 7.68 (m, 1H)

Example 25[2-(3-Fluoro-2-methyl-benzyl)-6-(2-hydroxy-ethoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[6-(2-Benzyloxy-ethoxy)-2-(3-fluoro-2-methyl-benzyl)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 12,step 1, using benzyl 2-bromo-ethyl ether. Yield: 26 mg.

LC/MS (method LC4): m/z=678

Step 2:[2-(3-Fluoro-2-methyl-benzyl)-6-(2-hydroxy-ethoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

The compound of step 1 (20 mg, 30 μmol) was dissolved in ethanol (5 ml),palladium on carbon (4 mg) was added, and the mixture was stirred underan atmosphere of hydrogen at a pressure of 1.5 bar at room temperaturefor 3 h. The mixture was filtered over a pad of celite and evaporatedunder reduced pressure. The residue was dissolved in DCM (20 ml), TFA (5ml) was added, and the mixture was stirred at room temperature for 1 h.The solvents were evaporated and the obtained solid was purified bypreparative HPLC. The eluate was lyophilized overnight, the residuedissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1M) and lyophilized overnight. 4 mg of the title compound were obtainedin the form of the[2-(3-fluoro-2-methyl-benzyl)-6-(2-hydroxy-ethoxy)-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride.

LC/MS (method LC4): m/z=488.20; Rt=1.10 min

Example 262-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carbonitrile

Step 1:4-(6-Bromo-2-chloro-1-phenyl-1H-indole-3-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 13,steps 1 to 5, starting with 6-bromo-1H-indole.

LC/MS (method LC4): m/z=518.84; Rt=1.95 min

Step 2:4-[6-Bromo-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 1 (1 g, 1.93 mmol), the title compound wasobtained analogously as described in example 1, step 2. Yield: 700 mg.

LC/MS (method LC4): m/z=609.20; Rt=2.10 min

Step 3:4-[6-Cyano-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

A mixture of the compound of step 2 (350 mg, 0.58 mmol), zinc cyanide(135 mg, 1.15 mmol) and tetrakis(triphenylphosphin)palladium(0) (133 mg,0.12 mmol) in DMF (8 ml) was heated to 80° C. for 1 h. After cooling toroom temperature, the mixture was partitioned between water and EA andthe aqueous phase extracted with EA. The combined organic layers weredried over sodium sulfate, filtered and concentrated. The residue waspurified by preparative HPLC and lyophilized overnight. 151 mg of thetitle compound were obtained.

LC/MS (method LC4): m/z=555

¹H-NMR: δ (ppm)=1.40 (m, 9H), 2.10 (m, 3H), 3.19 (m, 4H), 3.45 (m, 4H),6.87 (m, 1H), 7.01 (m, 1H), 7.21 (m, 1H), 7.50-7.64 (m, 7H), 7.72 (m,1H)

Step 4:2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carbonitrile

The compound of step 3 (20 mg, 36 μmol) was dissolved in DCM (6 ml), TFA(2 ml) was added, and the mixture was stirred at room temperature for 1h. The solvents were evaporated. The residue was dissolved in a smallquantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilizedovernight. 11 mg of the title compound were obtained in the form of the2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carbonitrilehydrochloride.

LC/MS (method LC8): m/z=454.18; Rt=2.73 min

¹H-NMR: δ (ppm)=2.13 (m, 3H), 2.99 (m, 4H), 3.68 (m, 4H), 6.88 (m, 1H),6.98 (m, 1H), 7.21 (m, 1H), 7.52 (m, 1H), 7.56-7.67 (m, 6H), 7.80 (m,1H)

Example 272-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylicacid methyl ester

Step 1:3-(4-tert-Butoxycarbonyl-piperazine-1-carbonyl)-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-6-carboxylicacid methyl ester

A mixture of the compound of example 26, step 2, (100 mg, 0.16 mmol),triethylamine (166 mg, 1.6 mmol), 1,3-bis(diphenylphosphino)propane (7.4mg, 18 μmol) and palladium(II) acetate (3.7 mg, 16 μmol) in DMF (8 ml)and MOH (2 ml) was heated to 120° C. for 2 h under an atmosphere ofcarbon monoxide. After cooling to room temperature, the mixture waspartitioned between water and EA. The aqueous phase was extracted withEA. The combined organic layers were dried over sodium sulfate,filtered, and concentrated. The residue was purified by silica gelchromatography (EA/HEP). 30 mg of the title compound were obtained.

LC/MS (method LC4): m/z=588

Step 2:2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylicacid methyl ester

From the compound of step 1 (10 mg, 17 μmol), the title compound wasprepared analogously as described in example 26, step 4, and obtained inthe form of the2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylicacid methyl ester hydrochloride. Yield: 8.8 mg.

LC/MS (method LC7): m/z=487.19; Rt=1.50 min

¹H-NMR: δ (ppm)=1.12 (m, 3H), 2.99 (m, 4H), 3.70 (m, 4H), 3.82 (m, 3H),6.87 (m, 1H), 6.97 (m, 1H), 7.21 (m, 1H), 7.55 (m, 1H), 7.58-7.64 (m,4H), 7.73 (m, 2H), 7.87 (m, 1H)

Example 282-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylicacid

The compound of example 27, step 1 (18 mg, 30.6 μmol) was dissolved inMOH (1 ml), a 2 N sodium hydroxide solution (300 μl) was added, and themixture was stirred at 40° C. for 3 h. The mixture was diluted with EAand washed with a saturated solution of ammonium chloride. The organiclayer was dried over sodium sulfate and concentrated. The residue wasdissolved in DCM (1 ml), TFA (0.3 ml) was added, and the mixture wasstirred at room temperature for 1 h. The solvents were evaporated andthe obtained solid residue was purified by preparative HPLC. The eluatewas lyophilized overnight. The residue was dissolved in a small quantityof MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight.3.6 mg of the title compound were obtained in the form of the2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carboxylicacid hydrochloride.

LC/MS (method LC4): m/z=474.20; Rt=1.11 min

¹H-NMR: δ (ppm)=2.14 (m, 3H), 3.12 (m, 4H), 3.86 (m, 4H), 6.69-6.80 (m,2H), 7.15 (m, 1H), 7.48-7.60 (5H), 7.71 (m, 1H), 7.89 (m, 1H), 7.95 (m,1H)

Example 292-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-5-carboxylicacid amide

A mixture of4-[5-cyano-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester (70 mg, 0.126 mmol), acetamide (31.5 mg, 0.53mmol) and palladium(II) chloride (2.2 mg, 13 μmol) in THF (4 ml) andwater (1.4 ml) was stirred at room temperature for 30 h. After additionof water, the mixture was extracted with EA. The combined organic layerswere dried over sodium sulfate and concentrated. The residue wasdissolved in DCM (1 ml), TFA (0.3 ml) was added, and the mixture wasstirred at room temperature for 1 h. The solvents were evaporated andthe obtained solid was purified by preparative HPLC. The eluate waslyophilized overnight. The residue was dissolved in a small quantity ofMOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight.13.5 mg of the title compound were obtained in the form of the2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-5-carboxylicacid amide hydrochloride.

LC/MS (method LC4): m/z=473.20; Rt=1.13 min

¹H-NMR: δ (ppm)=2.15 (m, 3H), 3.17 (m, 4H), 3.88 (m, 4H), 6.67 (m, 1H),6.74 (m, 1H), 7.13 (m, 1H), 7.28 (m, 1H), 7.45-7.58 (m, 5H), 7.80 (1),8.25 (m, 1H)

Example 30[2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indol-6-yloxy]-aceticacid

Step 1:4-[6-tert-Butoxycarbonylmethoxy-2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound was prepared analogously as described in example 12,step 1, using tert-butyl bromoacetate.

LC/MS (method LC4): m/z=660

Step 2:[2-(5-Fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indol-6-yloxy]-aceticacid

The compound of step 1 (88 mg, 133 μmol) was dissolved in DCM (20 ml),TFA (5 ml) was added, and the mixture was stirred at room temperaturefor 1 h. The solvents were evaporated and the obtained solid waspurified by preparative HPLC. The eluate was lyophilized overnight. Theresidue was dissolved in a small quantity of MOH, mixed withhydrochloric acid (0.1 M) and lyophilized overnight. 45 mg of the titlecompound were obtained in the form of the[2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indol-6-yloxy]-aceticacid hydrochloride.

LC/MS (method LC6): m/z=503.19; Rt=2.67 min

¹H-NMR: δ (ppm)=2.09 (m, 3H), 3.03 (m, 4H), 3.18 (m, 4H), 4.13 (m, 2H),6.66 (m, 2H), 6.79 (m, 1H), 6.93 (m, 1H), 7.16 (m, 1H), 7.43-7.60 (m,6H), 8.92 (m, 1H)

Example 31[2-(5-Fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1: 2-Chloro-6-methanesulfonyl-1-phenyl-1H-indole-3-carbaldehyde

The title compound was prepared analogously as described in example 13,steps 1 to 3, starting with 6-methanesulfonyl-1H-indole.

LC/MS (method LC4): m/z=472; Rt=1.40 min

Step 2:[2-(5-Fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1, the title compound was prepared analogouslyas described in example 1, step 2. Yield: 25 mg.

LC/MS (method LC4): m/z=424

Step 3:2-(5-Fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indole-3-carboxylicacid

From the compound of step 2, the title compound was prepared analogouslyas described in example 7, step 3. Yield: 23 mg.

LC/MS (method LC4): m/z=440

Step 4:4-[2-(5-Fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of step 3, the title compound was prepared analogouslyas described in example 17, step 1. Yield: 30 mg.

LC/MS (method LC4): m/z=608

Step 5:[2-(5-Fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 4 (30 mg, 49 μmol), the title compound wasprepared analogously as described in example 26, step 4, and obtained inthe form of the[2-(5-fluoro-2-methyl-phenoxy)-6-methanesulfonyl-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride. Yield: 9 mg.

LC/MS (method LC7): m/z=507.16; Rt=2.55 min

¹H-NMR: δ (ppm)=2.11 (m, 3H), 3.01 (m, 4H), 3.20 (m, 3H), 3.69 (m, 4H),6.88 (m, 1H), 6.98 (m, 1H), 7.22 (m, 1H), 7.55 (m, 1H), 7.62 (m, 5H),7.78 (m, 1H), 7.87 (m, 1H)

Example 32[1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanone

Step 1:4-[1-Cyclohex-2-enyl-2-(3-fluoro-2-methyl-benzyl)-1H-indole-3-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester

From the compound of example 22, step 3, (90.0 mg, 203 μmol), the titlecompound was prepared analogously as described in example 13, step 6.Yield: 100 mg.

LC/MS (method LC4): m/z=532

Step 2:[1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanone

From the compound of step 1 (90.0 mg, 169 μmol), the title compound wasprepared analogously as described in example 23, steps 1 and 2, andobtained in the form of the[1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanonehydrochloride. Yield: 30 mg.

LC/MS (method LC4): m/z=433.25; Rt=2.20 min

¹H-NMR: δ (ppm)=1.08 (m, 2H), 1.26 (m, 1H), 1.43 (m, 2H), 1.58 (m, 1H),1.74 (m, 2H), 2.16 (m, 2H), 2.31 (m, 3H), 2.95 (m, 2H), 3.18 (m, 2H),3.64 (m, 2H), 3.69 (m, 2H), 3.85 (m, 1H), 4.30 (m, 2H), 6.58 (m, 1H),6.95-7.10 (m, 2H), 7.17 (m, 2H), 7.53 (m, 1H), 7.70 (m, 1H)

Example 33[2-(3-Fluoro-2-methyl-benzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl]-piperazin-1-yl-methanone

The title compound was prepared analogously as described in the examplesabove, starting with the reaction of 1 equivalent each of2-chloro-1H-indole-3-carbaldehyde and 4-iodo-tetrahydro-2H-pyran in thepresence of potassium carbonate as a base in DMF at 100° C. for 4 h andpurification of the obtained2-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-3-carbaldehyde bypreparative HPLC, and obtained in the form of the[2-(3-fluoro-2-methyl-benzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt.

LC/MS (method LC8): m/z=435.23; Rt=2.65 min

Example 34[1-Cyclopentyl-2-(3-fluoro-2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanone

The title compound was prepared analogously as described in the examplesabove, starting with the reaction of 1 equivalent each of2-chloro-1H-indole-3-carbaldehyde and iodocyclopentane in the presenceof potassium carbonate as a base in DMF at 100° C. for 2 h andpurification of the obtained2-chloro-1-cyclopentyl-1H-indole-3-carbaldehyde by preparative HPLC, andobtained in the form of the[1-cyclopentyl-2-(3-fluoro-2-methyl-benzyl)-1H-indol-3-yl]-piperazin-1-yl-methanonetrifluoroacetic acid salt.

LC/MS (method LC8): m/z=419.24; Rt=2.94 min

Analogously as described in the examples above, the compounds of theformula Id listed in table 1 were prepared and obtained in the form oftheir trifluoroacetic acid salt or hydrochloride, respectively. Thecompounds can be named as [2-(R²⁰-oxy)-1-R³⁰-(4-R⁴⁰- and/or 5-R⁴⁰-and/or 6-R⁴⁰- and/or 7-R⁴⁰)-1H-indol-3-yl]-piperazin-1-yl-methanone incase the group A is O, or [2-(R²⁰-methyl)-1-R³⁰-(4-R⁴⁰- and/or 5-R⁴⁰-and/or 6-R⁴⁰- and/or 7-R⁴⁰)-1H-indol-3-yl]-piperazin-1-yl-methanone incase the group A is CH₂, allowing for modifications due to the rules ofnomenclature such as the designation of the group R²⁰-methyl as benzylgroup, for example.

TABLE 1 Example compounds of the formula Id Substituents Example R⁴⁰ andtheir Rt MS LC/MS no. A R²⁰ R³⁰ positions (min) (m/z) method 35 (1) Ophenyl phenyl 6-chloro 1.47 431.14 LC1 36 (1) O 2-methyl-phenyl phenyl6-methoxy 1.36 441.21 LC1 37 (1) O 5-fluoro-2-methyl- phenyl 6-methoxy1.40 459.20 LC1 phenyl 38 (1) O 3-fluoro-2-methyl- phenyl 6-methoxy 1.40459.20 LC1 phenyl 39 (1) CH₂ 3-fluoro-2-methyl- phenyl 7-fluoro 1.65445.20 LC2 phenyl 40 (1) CH₂ 3-fluoro-2-methyl- phenyl 6-methoxy 1.63457.22 LC2 phenyl 41 (1) O 3-fluoro-2-methyl- phenyl 7-fluoro 1.63447.18 LC2 phenyl 42 (1) O 5-fluoro-2-methyl- phenyl 7-fluoro 1.63447.18 LC2 phenyl 43 (1) O 3-fluoro-2-methyl- phenyl 5-methoxy 1.62459.20 LC2 phenyl 44 (1) O 5-fluoro-2-methyl- phenyl 5-methoxy 1.43459.20 LC1 phenyl 45 (2) CH₂ 3-fluoro-2-methyl- phenyl 5-hydroxy 1.34443.20 LC1 phenyl 46 (1) O 5-fluoro-2-methyl- 4-fluoro- 6-methoxy 1.42477.19 LC1 phenyl phenyl 47 (1) O 3-fluoro-2-methyl- 4-fluoro- 6-methoxy1.43 477.19 LC1 phenyl phenyl 48 (2) O 5-fluoro-2-methyl- 4-fluoro-6-hydroxy 1.48 463.17 LC3 phenyl phenyl 49 (2) CH₂ 3-fluoro-2-methyl-phenyl 5-hydroxy 1.35 443.20 LC1 phenyl 50 (2) CH₂ 3-fluoro-2-methyl-phenyl 6-hydroxy 1.29 443.20 LC1 phenyl 51 (2) O 5-fluoro-2-methyl-phenyl 5-hydroxy 1.32 445.18 LC1 phenyl 52 (1) O 5-fluoro-2-methyl-phenyl 5,6-dimethoxy 1.38 489.21 LC1 phenyl 53 (2) O 5-fluoro-2-methyl-phenyl 5-bromo 1.50 507.10 LC1 phenyl 54 (2) O 5-fluoro-2-methyl- phenyl6-methoxy 1.40 459.20 LC1 phenyl 55 (2) CH₂ 3-fluoro-2-methyl- phenyl4-methyl, 1.46 471.23 LC1 phenyl 5-methoxy 56 (2) CH₂ 3-fluoro-2-methyl-phenyl 4-methyl, 1.31 457.22 LC1 phenyl 5-hydroxy 57 (2) CH₂3-fluoro-2-methyl- phenyl 6-(2-phenoxy- 1.64 563.26 LC1 phenyl ethoxy)58 (2) O 5-fluoro-methyl- phenyl 6-bromo 3.09 507.10 LC6 phenyl 59 (2) O5-fluoro-methyl- phenyl 5-cyano 2.76 454.18 LC8 phenyl 60 (1) CH₂2-chloro-6-fluoro- phenyl 5-hydroxy 2.60 463.15 LC5 phenyl 61 (1) CH₂2-fluoro-6-methyl- phenyl 5-hydroxy 2.60 443.20 LC5 phenyl 62 (1) CH₂3-fluoro-2-methyl- phenyl 5-hydroxy, 3.19 565.25 LC5 phenyl6-(3-fluoro-2- methyl-benzyl) 63 (2) CH₂ 3-fluoro-2-methyl- phenyl6-methanesulfonyl 1.13 506.20 LC4 phenyl 64 (1) O 5-fluoro-2-methyl-phenyl 5-hydroxy, 2.78 479.14 LC5 phenyl 6-chloro 65 (2) O5-fluoro-2-methyl- phenyl 6-carbamoyl 2.54 472.19 LC6 phenyl 66 (3) O5-fluoro-2-methyl- phenyl 6-(2-dimethyl- 2.40 516.25 LC6 phenylamino-ethoxy) 67 (1) CH₂ 2-chloro-6-methyl- phenyl 5-hydroxy 2.90 459.17LC8 phenyl 68 (1) O 2,6-dimethyl-phenyl phenyl 5-hydroxy, 3.70 475.17LC9 6-chloro 69 (1) O 5-fluoro-2-methyl- phenyl 6-carboxy 2.65 473.18LC6 phenyl 70 (1) O 3-fluoro-2,6- phenyl 6-hydroxy 2.77 459.20 LC8dimethyl-phenyl (1) Obtained in the form of the trifluoroacetic acidsalt (2) Obtained in the form of the hydrochloride (3) Obtained in theform of the dihydrochloride

Analogously as described in the examples above, the compounds of theformula Ie listed in table 2 were prepared and obtained in the form oftheir trifluoroacetic acid salt unless specified otherwise. Thecompounds can be named as[2-(R²⁰-oxy)-1-R³⁰-1H-indol-3-yl]-piperazin-1-yl-methanone in case thegroup A is O, or[2-(R²⁰-sulfanyl)-1-R³⁰-1H-indol-3-yl]-piperazin-1-yl-methanone in casethe group A is S, or[2-(R²⁰-methyl)-1-R³⁰-1H-indol-3-yl]-piperazin-1-yl-methanone in casethe group A is CH₂, allowing for modifications due to the rules ofnomenclature such as the designation of the group R²⁰-methyl as benzylgroup, for example.

TABLE 2 Ie

Example compound of the formula Ie Rt MS LC/MS Example no. A R²⁰ R³⁰(min) (m/z) method 71 O 3-methyl-phenyl phenyl 1.37 411.19 LC1 72 O3-fluoro-phenyl phenyl 1.35 415.17 LC1 73 O 4-fluoro-phenyl phenyl 1.35415.17 LC1 74 O 2-fluoro-phenyl phenyl 1.35 415.17 LC1 75 CH₂ phenylphenyl 1.53 395.20 LC2 76 O 2-ethyl-phenyl phenyl 1.70 425.21 LC2 77 O2-isopropyl-phenyl phenyl 1.50 439.23 LC1 78 O 2-methoxy-phenyl phenyl1.32 427.19 LC1 79 O 2,6-dimethyl-phenyl phenyl 1.42 425.21 LC2 80 O2-chloro-phenyl phenyl 1.31 431.14 LC1 81 CH₂ 2-methyl-phenyl phenyl1.24 410.25 LC4 82 CH₂ 2-fluoro-phenyl phenyl 1.23 414.20 LC4 83 CH₂3-methyl-phenyl phenyl 1.40 409.22 LC1 84 O 3-trifluoromethyl-phenylphenyl 1.57 465.17 LC3 85 O 3-chloro-phenyl phenyl 1.24 432.20 LC4 86 Sphenyl phenyl 1.35 413.16 LC1 87 CH₂ 2,6-difluoro-phenyl phenyl 1.37431.18 LC1 88 CH₂ 2-chloro-phenyl phenyl 1.41 429.16 LC1 89 O phenyl3-(3-methoxy- 1.60 485.23 LC2 propoxy)-phenyl 90 O 2-methyl-phenyl3-(3-methoxy- 1.65 499.25 LC2 propoxy)-phenyl 91 O phenyl4-fluoro-phenyl 1.53 415.17 LC2 92 O 2-methyl-phenyl 2-methoxy-phenyl1.55 441.21 LC2 93 O phenyl 2-methoxy-phenyl 1.49 427.19 LC2 94 O2-methyl-phenyl pyridin-3-yl 1.15 412.19 LC2 (1) 95 O phenylpyridin-3-yl 1.07 398.17 LC2 (1) 96 O 2-methyl-phenyl 4-fluoro-phenyl1.63 429.19 LC2 97 O 2-methyl-phenyl 2-(3-methoxy- 1.60 499.25 LC2propoxy)-phenyl 98 O phenyl 2-(3-methoxy- 1.57 485.23 LC2propoxy)-phenyl 99 O 3-fluoro-2-methyl-phenyl phenyl 1.44 429.19 LC1 100S 3-fluoro-phenyl phenyl 1.47 431.15 LC1 101 S 2-fluoro-phenyl phenyl1.41 431.15 LC1 102 O 2-fluoro-6-methyl-phenyl phenyl 1.48 429.19 LC1103 O 2-fluoro-phenyl 2-(3-methoxy- 1.36 504.20 LC4 propoxy)-phenyl 104O 2-methyl-phenyl pyridin-2-yl 1.23 412.19 LC1 (1) 105 O phenylpyridin-2-yl 1.20 398.17 LC1 (1) 106 O 2,3-difluoro-phenyl phenyl 1.38433.16 LC1 107 O 2,5-difluoro-phenyl phenyl 1.38 433.16 LC1 108 S2-methyl-phenyl phenyl 1.42 427.17 LC1 109 O 5-fluoro-2-methyl-phenylthiophen-3-yl 1.41 435.14 LC1 110 O 3,5-difluoro-2-methyl- phenyl 1.47447.18 LC1 phenyl 111 O 3-fluoro-2-methyl-phenyl 6-methoxy-pyridin- 1.37460.19 LC1 (1) 3-yl 112 O 5-fluoro-2-methyl-phenyl 6-methoxy-pyridin-1.39 460.19 LC1 (1) 3-yl 113 CH₂ 2-methyl-phenyl thiophen-3-yl 1.42415.17 LC1 114 CH₂ 3-fluoro-2-methyl-phenyl 6-methoxy-pyridin- 1.37458.21 LC1 (1) 3-yl 115 CH₂ 3-fluoro-2-methyl-phenyl 2-(2-methoxy- 1.62501.24 LC2 ethoxy)-phenyl 116 CH₂ 3-fluoro-2-methyl-phenyl6-hydroxy-pyridin- 1.03 444.20 LC2 (2) 3-yl 117 O5-fluoro-2-methyl-phenyl 3-methoxy-phenyl 1.32 460.19 LC1 118 O5-fluoro-2-methyl-phenyl 3-hydroxy-phenyl 1.00 446.18 LC1 119 O5-fluoro-2-methyl-phenyl 4-methyl-phenyl 3.01 443.20 LC6 120 O5-fluoro-2-methyl-phenyl tetrahydro-2H- 2.57 437.52 LC8 pyran-4-yl 121 O5-fluoro-2-methyl-phenyl cyclopentyl 2.96 421.22 LC8 122 O2,6-dimethyl-phenyl cyclopentyl 2.96 417.24 LC8 (1) Obtained in the formof the bis(trifluoroacetic acid salt) (2) Obtained in the form of thetrifluoroacetic acid salt; from 6-methoxy-pyridine-3-boronic acid asstarting compound through cleavage of the methoxy group.

Analogously as described in the examples above, the compounds of theformula If listed in table 3 were prepared and obtained in the form oftheir trifluoroacetic acid salt or hydrochloride, respectively. Thecompounds can be named as[2-phenoxy-1-phenyl-1H-indol-3-yl]-R¹⁰⁰-methanone.

TABLE 3 If

Example compounds of the formula If Rt MS LC/MS Example no. R¹⁰⁰ (min)(m/z) method 123 3-methyl-piperazin-1-yl 1.36 411.19 LC1 (1) 1243,3-dimethyl-piperazin-1-yl 2.00 425.21 LC5 (1) 1253-butyl-piperazin-1-yl 2.15 453.24 LC5 (1) 126 2-benzyl-piperazin-1-yl3.12 487.23 LC8 (1) (1) Obtained in the form of the trifluoroacetic acidsalt (2) Obtained in the form of the hydrochloride

Example 127[6-Chloro-2-(5-fluoro-2-methyl-phenoxy)-5-hydroxy-1-phenyl-1H-indol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanone

The title compound was prepared analogously as described in the examplesabove and obtained in the form of the[6-chloro-2-(5-fluoro-2-methyl-phenoxy)-5-hydroxy-1-phenyl-1H-indol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanonetrifluoroacetic acid salt.

LC/MS (method LC6): m/z=493.16; Rt=2.93 min

Pharmacological Tests A) Inhibition of Renin

The renin-inhibiting activity of compounds of the invention wasdemonstrated in an in vitro test in which a non-endogenous fluorogenicpeptide substrate is cleaved by renin specifically at the Leu-Val bondwhich corresponds to the cleavage site of angiotensinogen.

Recombinant human renin (Cayman, no. 10006217) at a concentration of 5nM was incubated with the test compounds at various concentrations andthe synthetic substrateDabcyl-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS (Bachem, no.M-2050; Dabcyl means the 4-(4-dimethylamino-phenylazo)-benzoyl group andEDANS means the amide with5-[(2-aminoethyl)amino]-naphthalene-1-sulfonic acid) at a concentrationof 10 μM for 2 h at room temperature in 0.05 M Tris buffer (pH 8)containing 0.1 M NaCl, 2.5 mM EDTA and 1.25 mg/ml bovine serum albumin.The increase in fluorescence, which is due to fluorescence resonanceenergy transfer, was recorded at an excitation wavelength of 330 nm andan emission wavelength of 485 nm in a microplate spectrofluorometer.Inhibitory concentrations IC₅₀ were calculated from the percentage ofinhibition of renin activity as a function of the concentration of thetest compound. In this test, the example compounds generally inhibitedrenin with an IC₅₀ value of less than about 10 micromol/l (10 μM).Representative IC₅₀ values, which were determined with the compounds inthe form of the obtained salt indicated in the examples above, arelisted in table 4.

TABLE 4 IC₅₀ values for inhibition of renin (fluorogenic peptidesubstrate) Compound of example no. IC₅₀ (μM) 3 3.2 5 3.4 17 0.018 220.0072 24 1.6 25 0.031 29 0.0055 30 0.13 32 0.034 33 0.75 35 0.54 390.084 40 0.012 48 0.018 56 0.0019 57 0.024 62 0.43 63 0.044 66 0.029 890.76 91 0.71 108 0.071 113 0.23 116 9.4 123 6.5 126 4.5

B) Inhibition of Renin in Human Plasma

The renin-inhibiting activity of compounds of the invention was alsodemonstrated in an in vitro test in the presence of human plasma. Theprocedure followed the procedure described in pharmacological test Aexcept that human recombinant renin at a concentration of 30 nM wasincubated with the test compounds at various concentrations and thefluorogenic substrateDabcyl-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS at aconcentration of 25 μM for 30 min at 37° C. and 30 min at roomtemperature in human plasma (Innovative Research, pooled normal humanplasma collected on EDTA K3 as an anticoagulant, no. IPLA-5).

C) Antihypertensive Activity

The in vivo antihypertensive activity of compounds of the invention canbe demonstrated in doubly transgenic mice overexpressing both humanrenin and angiotensinogen genes (dTghRenhAgt mice; cf. D. C. Merrill etal., J. Clin. Invest. 97 (1996), 1047; R. L. Davisson et al., J. Clin.Invest. 99 (1997), 1258; J. L. Lavoie et al., Acta Physiol. Scand. 81(2004), 571; available by breeding strains carrying the human renintransgene and the human angiotensinogen transgene, respectively).Briefly, in this test the arterial pressure in freely moving maledTghRenhAgT mice is determined by telemetry monitoring. For thispurpose, the catheter of a radio transmitter (model TA11PA-10, DSI) isimplanted into the left carotid artery of dTghRenhAgT mice underanesthesia. Animals are kept on a 12 h light/dark cycle and have freeaccess to food and water. After one week of recovery period, arterialpressure and heart rate are monitored over 24 h to establish thebaseline values. Then animals receive orally by gavage either the dailydose of the test compound in vehicle (water containing 0.6% ofmethylcellulose and 0.5% of Tween® 80) or, as a control, vehicle only.Hemodynamic parameters are recorded continuously for an additional 24 hand maximal mean arterial pressure lowering effect and duration ofantihypertensive activity are determined (mean arterialpressure=diastolic pressure+⅓·(systolic pressure−diastolic pressure)).Compounds are screened at various doses such as 3 mg/kg body weight and10 mg/kg body weight per day.

1. A compound of formula I or a stereoisomeric form thereof, or aphysiologically acceptable salt thereof, or a physiologically acceptablesolvate of any of them,

wherein A is chosen from O, S, N((C₁-C₄)-alkyl) and C(R^(a))₂; R^(a) ischosen from hydrogen, fluorine and (C₁-C₄)-alkyl, wherein the two groupsR^(a) are independent of each other and can be identical or different,or the two groups R^(a) together are a divalent (C₂-C₈)-alkyl group; Ris chosen from hydrogen, fluorine, (C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl-, heteroaryl-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)—, R¹—NH—CO—C_(u)H_(2u)— and(C₁-C₄)-alkyl-O—, wherein all groups R are independent of each other andcan be identical or different; R¹ is chosen from hydrogen,(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- and H₂N—CO—(C₁-C₄)-alkyl-, R¹⁰ ischosen from hydrogen, (C₁-C₆)-alkyl-O—CO— and(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—; R²⁰ is chosen from phenyl andheteroaryl which are optionally substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, hydroxy and cyano; R³⁰ ischosen from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, tetrahydropyranyl,phenyl and heteroaryl, wherein cycloalkyl and cycloalkenyl areoptionally substituted by one or more identical or differentsubstituents chosen from fluorine, (C₁-C₄)-alkyl and hydroxy, and phenyland heteroaryl are optionally substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, hydroxy-(C₁-C₆)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₆)-alkyl-,(C₁-C₄)-alkyl-CO—NH—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—, hydroxy-(C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-CO—NH—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano;R⁴⁰ is chosen from halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—, phenyl-(C₁-C₄)-alkyl-,heteroaryl-(C₁-C₄)-alkyl-, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₄)-alkyl-,phenyl-O—(C₁-C₄)-alkyl-, heteroaryl-O—(C₁-C₄)-alkyl-,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-, HO—CO—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-, H₂N—CO—(C₁-C₄)-alkyl-, hydroxy,(C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—,phenyl-(C₁-C₄)-alkyl-O—, heteroaryl-(C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, heteroaryl-O—(C₁-C₄)-alkyl-O—,di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—, HO—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—, H₂N—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₃-C₇)-cycloalkyl-C_(v)H_(2v)—CO—O—,(C₁-C₄)-alkyl-NH—CO—O—, (C₃-C₇)-cycloalkyl-C_(v)H₂, —NH—CO—O—,(C₁-C₄)-alkyl-S(O)_(m)—, nitro, amino, (C₁-C₄)-alkylamino,di((C₁-C₄)-alkyl)amino, (C₁-C₄)-alkyl-CO—NH—,(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—CO—NH—, (C₁-C₄)-alkyl-S(O)₂—NH—, HO—CO—,(C₁-C₄)-alkyl-O—CO—, H₂N—CO—, ((C₁-C₄)-alkyl)-NH—CO—,di((C₁-C₄)-alkyl)N—CO—, cyano, HO—S(O)₂—, H₂N—S(O)₂—,((C₁-C₄)-alkyl)-NH—S(O)₂— and di((C₁-C₄)-alkyl)N—S(O)₂—, wherein allsubstituents R⁴⁰ are independent of each other and can be identical ordifferent; heteroaryl is an aromatic monocyclic, 5-membered or6-membered, heterocyclic group which comprises 1, 2 or 3 identical ordifferent ring heteroatoms chosen from N, O and S, wherein one of thering nitrogen atoms can carry a hydrogen atom or a (C₁-C₄)-alkyl group,and wherein the heteroaryl group is bonded via a ring carbon atom; m is0, 1 or 2, wherein all numbers m are independent of each other and canbe identical or different; n is 0, 1, 2, 3 or 4; p and q, which areindependent of each other and can be identical or different, are 2 or 3;u is 0, 1 or 2, wherein all numbers u are independent of each other andcan be identical or different; v is 0, 1 or 2, wherein all numbers v areindependent of each other and can be identical or different; wherein allalkyl groups, independently of each other, are optionally substituted byone or more fluorine atoms; wherein all cycloalkyl groups, independentlyof each other, are optionally substituted by one or more identical ordifferent substituents chosen from fluorine and (C₁-C₄)-alkyl, unlessspecified otherwise; and wherein all phenyl and heteroaryl groupspresent in R and R⁴⁰, independently of each other, are optionallysubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)₂— andcyano.
 2. A compound as claimed in claim 1, wherein p is 2 and q is 2 or3.
 3. A compound as claimed in claim 1, wherein R⁴⁰ is chosen fromhalogen, (C₁-C₄)-alkyl, phenyl-(C₁-C₄)-alkyl-, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,HO—CO—(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—CO—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, (C₁-C₄)-alkyl-S(O)_(m)—,HO—CO—, (C₁-C₄)-alkyl-O—CO—, H₂N—CO— and cyano, wherein all substituentsR⁴⁰ are independent of each other and can be identical or different. 4.A compound as claimed in claim 1, wherein A is chosen from O, S andC(R^(a))₂; R^(a) is chosen from hydrogen, fluorine and methyl, whereinthe two groups R^(a) are independent of each other and can be identicalor different, or the two groups R^(a) together are a divalent(C₂-C₅)-alkyl group; R is chosen from hydrogen, (C₁-C₄)-alkyl,hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— andR¹—NH—CO—C_(u)H_(2u)—, wherein all groups R are independent of eachother and can be identical or different; R¹ is chosen from(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl- and H₂N—CO—(C₁-C₄)-alkyl-; R¹⁰ ischosen from hydrogen, (C₁-C₆)-alkyl-O—CO— and(C₃-C₇)-cycloalkyl-C_(v)H_(2v)—O—CO—; R²⁰ is chosen from phenyl andheteroaryl which are optionally substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₄)-alkyl,(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S(O)_(m)—, hydroxy and cyano; R³⁰ ischosen from (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, tetrahydropyranyl,phenyl and heteroaryl, wherein cycloalkyl and cycloalkenyl areoptionally substituted by one or more identical or differentsubstituents chosen from fluorine, (C₁-C₄)-alkyl and hydroxy, and phenyland heteroaryl are optionally substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₆)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-, hydroxy, (C₁-C₆)-alkyl-O—,(C₁-C₄)-alkyl-O—(C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S(O)_(m)— and cyano; R⁴⁰is chosen from halogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-, hydroxy, (C₁-C₄)-alkyl-O—,hydroxy-(C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-O—,phenyl-O—(C₁-C₄)-alkyl-O—, di((C₁-C₄)-alkyl)N—(C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-CO—O—, (C₁-C₄)-alkyl-NH—CO—O—, HO—CO—, (C₁-C₄)-alkyl-O—CO—and H₂N—CO—, wherein all substituents R⁴⁰ are independent of each otherand can be identical or different; heteroaryl is chosen from thiophenyland pyridinyl; m is 0, 1 or 2, wherein all numbers m are independent ofeach other and can be identical or different; n is 0, 1 or 2; p and qare 2; u is 0, 1 or 2, wherein all numbers u are independent of eachother and can be identical or different; v is 0, 1 or 2; wherein allalkyl groups, independently of each other, are optionally substituted byone or more fluorine atoms; wherein the cycloalkyl group is optionallysubstituted by one or more identical or different substituents chosenfrom flourine and (C₁-C₄)-alkyl, unless specified otherwise; and whereinall phenyl groups present in R and R⁴⁰, independently of each other, areoptionally substituted by one or more identical of differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)₂— and cyano.
 5. A compound as claimed in claim 4,wherein one, two or three of the groups R, which are independent of eachother and can be identical or different, are chosen from hydrogen,(C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—(C₁-C₄)-alkyl-,phenyl-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—CO—C_(u)H_(2u)— andR¹—NH—CO—C_(u)H_(2u)—, and all other groups R are hydrogen.
 6. Acompound as claimed in claim 5, wherein R²⁰ is phenyl which isoptionally substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyl-O—,(C₁-C₄)-alkyl-S(O)_(m)—, hydroxy and cyano.
 7. A process for thepreparation of a compound as claimed in claim 1, comprising reacting acompound of formula XIV with a compound of formula X to give a compoundof formula XIII,

wherein A, R, R²⁰, R³⁰, R⁴⁰, n, p and q are defined as in claim 1 and,additionally, functional groups can be present in protected form or inthe form of a precursor group, and R⁵⁰ is defined as R¹⁰ in claim 1,with the exception of hydrogen, or is a protective group, and removingthe protective group R⁵⁰ in the case of the preparation of a compound inwhich R¹⁰ is hydrogen.
 8. A pharmaceutical composition which comprisesat least one compound as claimed in claim 1 and a pharmaceuticallyacceptable carrier.
 9. A method for the treatment of hypertension, heartfailure, cardiac infarction, angina pectoris, cardiac insufficiency,cardiac hypertrophy, cardiac fibrosis, vascular hypertrophy, leftventricular dysfunction, restenosis, renal fibrosis, renal ischemia,renal failure, kidney insufficiency, nephropathy, retinopathy, ischemicor obstructive peripheral circulation disorder, glaucoma or end-organdamage, the method comprising administering to a patient in need thereofan effective dose of a compound as claimed in claim 1.